Polo-like kinases and UV-induced skin carcinogenesis: What we know and what's next.

INTRODUCTION
Skin cancer develops from the uncontrolled growth of skin cells, often triggered by ultraviolet (UV) radiation, among other contributing factors. UV radiation, an electromagnetic radiation (100–400 nm range) invisible to the human eye, is an established cause of inflammation, oxidative stress, and photo‐immunosuppression, contributing to various skin disorders, including melanoma and non‐melanoma skin cancers.
1
While the sun is the primary source of UV radiation, artificial sources such as tanning beds, mercury vapor lighting, etc., also contribute to organismal UV exposure. There are three main types of UV radiation, categorized as UVA, UVB, and UVC, based on their wavelengths. UVA (315–400 nm) penetrates deeply into the skin and is linked to premature aging and an increased risk of skin cancer. UVB radiation (280–315 nm) is primarily responsible for sunburn and significant skin damage, whereas UVC radiation (100–280 nm) is absorbed by the Earth's atmosphere and does not reach the surface. Prolonged exposure to UVB causes significant damage to DNA, proteins, and lipids and induces genomic instability.
2
UV (UVA/UVB) radiation is also known to cause DNA lesions affecting genes controlling cell division, resulting in malignant transformation.
3

The genomic integrity of cells is tightly regulated by multiple processes that control DNA replication, cell division, and survival of cells.
4
Failure to regulate these key processes in cell division results in genomic instability and is associated with the accumulation of mutations and chromosomal aberrations, which may lead to various diseases. Genomic instability is also a hallmark of cancer that can cause uncontrolled cell proliferation.
5
Mitotic protein kinases, such as cyclin‐dependent kinases (Cdks), aurora kinases, and polo‐like kinases (PLKs), are key players for error‐free cell division and genomic stability.
6
For the purpose of this review, we are focusing on polo‐like kinases (PLKs), a family of serine/threonine kinases including PLK1, PLK2, PLK3, PLK4, and PLK5. These kinases are characterized by an N‐terminal catalytic domain and the presence of either one (PLK4) or two (PLK1–3 and PLK5) highly conserved polo‐box domains, which are involved in subcellular localization, target binding, and cis‐acting regulation of PLK‐dependent biochemical processes. The PLK family plays crucial roles in cell cycle regulation, mitosis, cytokinesis, and other cellular processes.
7
Their dysregulation is implicated in various cancers, including melanomas and non‐melanoma skin cancers, and they are being investigated as potential therapeutic targets for anti‐cancer drug discovery. In this review, we discuss the role of PLKs in skin cancers. In addition, we delve into the potential association between UV, PLKs, and skin cancers.

UV RADIATION, SKIN, AND SKIN CANCER
UV radiation can significantly impact skin health by compromising the skin's protective functions, making it more vulnerable to irritation, inflammation, reduced elasticity, and injury. UV‐induced cutaneous damage can lead to mild to severe skin disorders, including skin cancers. UV radiation can have both short‐term and long‐term negative effects on the skin. Short‐term UV exposure can result in hyperpigmentation, changes in skin appearance, inflammation, acute dermatitis, and reduced skin elasticity, while long‐term exposure can accelerate premature skin aging, leading to wrinkles, hyperpigmentation, and a weakened immune system. Chronic UV radiation is also a known risk factor for the development of keratoacanthomas, melanoma, and non‐melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
1

The impact of UV radiation on the skin is particularly concerning due to the increasing number of cases of skin cancer worldwide.
8
UV exposure to skin can result in direct DNA damage, impaired DNA repair mechanisms, oxidative stress, and inflammatory responses (Mohania et al. and references therein).
9
This could lead to genetic mutations and changes in skin cells, which may contribute to skin cancer development and progression. Among multiple mechanisms, this can occur primarily through the formation of cyclobutane pyrimidine dimers (CPDs) and 6‐4 photoproducts (6‐4PPs) in DNA. Cells have mechanisms to repair UV‐induced CPDs and 6‐4PPs. However, unrepaired DNA damage can be highly mutagenic, altering the DNA sequence and contributing to genomic instability and cancer.
10
UV‐induced skin cancers are often linked to defective DNA repair mechanisms such as base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and homologous recombination (HR).
11
UV radiation frequently induces mutations at dipyrimidine sites in DNA, especially C>T transitions. These transitions are frequently found in cancer‐related genes, making them a key biomarker of UV‐induced skin cancers. For example, SCCs and BCCs commonly exhibit p53 mutations in dipyrimidine sites, reinforcing the close link between UV exposure and skin cancer.
12
,
13
Interestingly, mutations in the p53 gene are absent in non‐sun‐exposed regions of the body, further highlighting the significance of UV exposure in skin cancer‐related mutations. UVB radiation is particularly associated with melanoma and non‐melanoma skin cancers, where it causes DNA breaks, pyrimidine dimers, and cross‐linking of DNA.
14
,
15
Additionally, in response to UV‐induced DNA damage, keratinocytes may undergo apoptosis, preventing the proliferation of keratinocytes with DNA mutations or damage. These apoptotic keratinocytes are known as sunburn cells. It is a protective mechanism, and when it fails, it leads to the propagation of damaged cells and the risk of NMSC.
16

The effects of UV radiation are not limited to direct DNA damage but also involve complex cellular responses. UV exposure of skin leads to an inflammatory response and production of reactive oxygen species (ROS). Evidence shows that UVB results in functional defects in cell‐mediated immunity by altering the profiles of inflammatory cytokines in the epidermis, suppressing phagocytosis and increasing ROS production by keratinocytes, decreasing antigen presentation by Langerhans cells, and inducing early lymphocyte depletion and late T‐cell proliferation. Additionally, UV exposure to the skin increases the production of ROS, which can damage DNA and trigger cell injury and apoptosis.
17
This oxidative stress exacerbates the mutagenic effects of UV radiation, such as base pair mismatches, contributing to the accumulation of genetic errors that drive skin cancer progression. The damaging effects of UV‐induced ROS on the skin are also well documented in NMSCs and melanoma. UVB radiation‐induced oxidative stress can increase genetic instability, which accelerates the transformation of non‐malignant lesions into malignant ones.
14
,
15
The body has an innate antioxidant defense system to counteract ROS, including enzymes like glutathione peroxidase, superoxide dismutase (SOD), catalase (CAT), and glutathione (GST), as well as vitamins like ascorbic acid and tocopherol.
18
These antioxidants neutralize free radicals and maintain a healthy balance of ROS in the skin. However, excessive ROS production can overwhelm the antioxidant system, causing damage to cellular components such as nucleic acids, proteins, lipids, and enzymes, altering normal cellular function and contributing to skin disease.
18

The pigment melanin, a complex polymer derived from the amino acid tyrosine, serves as a protective mechanism in the skin by absorbing UV radiation to reduce DNA damage.
19
Melanin can undergo rapid oxidation as a stable free radical and acts as a biological exchange polymer. This increases the rate of pigment formation, providing additional protection against UV.
19
However, excessive UV radiation can overwhelm the protective capacity of melanin, leading to severe DNA damage, which is not adequately repaired in individuals with compromised DNA repair mechanisms, such as those with Xeroderma pigmentosum (XP).
20
The NER pathway is crucial for repairing UV‐induced DNA damage, especially the CPDs and 6‐4PPs. For instance, in individuals with XP, the impaired NER pathway results in the accumulation of UV‐induced DNA damage, which significantly increases their risk of developing skin cancer at an early age. XP‐related skin cancers have shown UV signature transition mutations, demonstrating the significance of UV‐induced damage and defective NER in skin disease.
21
Further, the hyperproliferation of the melanin‐producing melanocytes leads to melanoma. Its risk is influenced by genetic factors such as mutations in the melanocortin‐1 receptor (MC1R) gene, which is involved in skin pigmentation and UV susceptibility.
22
Individuals with lighter skin, who have less melanin to protect against UV damage, are particularly vulnerable to melanoma.
23
The MC1R gene also plays a role in enhancing the NER pathway and oxidative resistance, suggesting that modulating MC1R signaling could offer potential therapeutic strategies to reduce UV vulnerability.
22

Despite the harmful effects of UV radiation, controlled exposure can have health benefits, such as improved mood, enhanced appearance, and the synthesis of vitamin D, which has numerous health benefits.
9
Phototherapy, combining psoralen plus ultraviolet A radiation (PUVA) therapy, is also used to treat several skin conditions. However, the overwhelming evidence of UV radiation's contribution to skin cancer highlights the need for effective UV protection and continued research into the mechanisms underlying UV‐induced skin cancer, as well as potential management options.
Overall, UV radiation triggers a complex interplay of genetic mutations and cellular mechanisms that contribute to skin cancer development. Understanding these and other underlying mechanisms is crucial for advancing strategies to reduce the incidence of UV‐induced skin malignancies and improve public health outcomes. One of the emerging mechanisms in skin cancer development is PLK signaling. In the following section, we discuss the involvement of various PLK family members in UV‐associated skin cancers.

ROLE OF POLO‐LIKE KINASES IN UV‐ASSOCIATED SKIN CANCERS
Polo‐like kinases are known to regulate a variety of important cellular processes such as centriole duplication, centrosome maturation, mitosis, cytokinesis, and cell cycle progression in mammalian cells. PLKs are associated with the development and progression of a variety of cancers (reviewed in
24
). There is ample evidence showing the involvement of PLK family members in melanoma as well as non‐melanoma skin cancers. Although PLK1 is the most well‐studied member of the PLK family, other members are also becoming increasingly attractive targets of investigation for their roles in various skin cancers. Below, we will discuss the role of PLK family members in different UV‐associated skin cancers, including melanoma and non‐melanoma skin cancers (Figure 1).

Melanoma
Melanoma is one of the most aggressive and deadly forms of skin cancer and is the fifth most common cancer among the adult population. In 2025, an estimated 107,240 new melanoma cases and 8430 melanoma‐related deaths are predicted in the United States.
8
Melanoma pathogenesis encompasses a complex interaction between environmental factors, particularly UV radiation, genetic mutations, and epigenetic modifications that alter melanocytes into invasive cancer cells. Oncogenic BRAF, NRAS, KIT, and MITF mutations are present in melanoma, where the BRAF

V600E

mutation is found in around 60% of melanoma patients.
25
Analysis of large‐scale melanoma exome data has discovered novel UV‐mediated mutations in PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2 genes.
25
Chronic UV exposure and genetic mutations in genes like BRAF and NRAS may lead to uncontrolled cell proliferation and melanocytic transformation. Other mutations in pigmentation‐related genes, cell‐cycle regulators, and epigenetic factors further contribute to melanoma development.
25

Studies have revealed distinct roles of different members of the PLK family in melanoma development and progression. PLK1 was shown to be overexpressed in several cancers, including melanoma, and is being investigated as a viable target for cancer management. Studies from our laboratory and by others have shown that PLK1 is overexpressed in both clinical tissue specimens and human melanoma cells when compared with normal skin tissues and melanocytes, respectively.
26
,
27
,
28
A study by Cholewa et al. from our lab, used Vectra immunostaining technology to assess the expression profile of PLK1 in benign nevi and metastatic melanomas. They also found significant overexpression of PLK1 in melanoma tissues.
28
Moreover, Kneisel et al. have demonstrated that malignant melanomas with metastases expressed PLK1 at distinctly higher levels compared to melanomas without metastases, making it a reliable marker to identify patients at high risk for metastases.
29
Similarly, gene microarray data from another study revealed relatively low expression of PLK1 in melanocytic nevi. The expression was significantly higher in primary melanomas and was highest in melanoma metastases
30
further supporting the role of PLK1 levels as a reliable biomarker for melanoma progression. Interestingly, overexpression of PLK1 in melanoma cells was also associated with exposure to arsenic, a known carcinogen. Li et al. reported that treatment of A375 melanoma cells with low‐dose sodium arsenite resulted in increased expression of PLK1 at both mRNA and protein levels.
31
Although it remains to be elucidated what other carcinogens could affect the levels of PLK1 expression in melanoma, the initial studies seem to corroborate the potential of targeting PLK1 for better melanoma management.
Several studies have assessed the effect of PLK1 inhibition on melanoma in vivo and in vitro in different melanoma models. For example, we have earlier demonstrated that genetic as well as small molecular inhibition of PLK1 led to a mitotic catastrophe, G2/M phase cell cycle arrest, and apoptosis in multiple human melanoma cell lines.
26
,
28
Further, Jalili et al. found that PLK1 knockdown or inhibition using the PLK1 small molecule inhibitor BI 2536 in multiple human melanoma cell lines could lead to decreased cell viability and induction of apoptosis.
30
Oliveira et al. also found that PLK1 small molecule inhibition significantly decreased cell proliferation and clonogenicity, promoting cell cycle arrest in the G2/M phase in melanoma cells.
32
The potential of targeting PLK1 for better melanoma management was further validated by studies from our lab, where proteomics technology was used to analyze the proteome of BRAF

V600E
mutant melanoma cells after treatment with another PLK1 inhibitor, BI 6727. We identified more than 20 proteins of interest, most of which were not previously associated with PLK1 signaling. Further, PLK1 inhibition resulted in downregulation of multiple proteasomal subunits and multiple metabolic proteins, including lactate dehydrogenase and glucose‐6‐phosphate isomers.
33
Using the PLK1 inhibitor BI 6727 on the xenograft mouse model, Cholewa et al. showed a significant tumor growth delay and regression in vivo on treatment with BI 6727. This was further accompanied by increased p53 expression, reduction in proliferation markers, and induction of apoptosis.
28
Another study from our laboratory demonstrated that PLK1 was also associated with changes in cellular metabolism‐associated genes, where its knockdown by shRNA in A375 melanoma cells resulted in a significant downregulation of IDH1, PDP2, and PCK1 and upregulation of FBP1. This was also confirmed in a xenograft model implanted with melanoma cells, where a decrease in PCK1 and an increase in FBP1 were observed after BI 6727 treatment. This suggests a metabolic shift that occurs after PLK1 knockdown or inhibition. The shift could be related to changes in glucose metabolism, energy production, and other metabolic pathways
34
and could be harnessed for effective melanoma management.
A major challenge with malignant melanomas is that they develop resistance to BRAF and MEK‐targeted therapies (reviewed in
35
). PLK1 inhibitors in combination with other targeted inhibitors have shown superior effectiveness in melanoma management. Screening of a library of kinase inhibitors identified a synergistic interaction between BRAF and PLK1 inhibition. Interestingly, treatment of A375 melanoma cells with dabrafenib in combination with BI 6727 showed a significant reduction in cell proliferation as compared to individual treatments.
36
Uebel et al. demonstrated similar efficacy in resistant cell lines. It was observed that the combination of vemurafenib and BI 6727 in resistant A375R cells with BRAF

V600E
mutation showed a synergistic effect on decreasing cell viability and inducing apoptosis as compared to vemurafenib alone.
37

Besides BRAF, a study has shown that MAPK inhibition induced cell cycle arrest at the G1 phase and decreased PLK1 protein levels. In this study, the melanoma cells were treated with PD98059, a MEK1/2 inhibitor, and BI 2536. The combination of both compounds significantly suppressed melanoma cell viability in vitro.
30
Similarly, a study from our laboratory demonstrated a synergistic antiproliferative response to a combination of PLK1 and NOTCH inhibitors in human melanoma cells. Further analysis of a human tissue microarray containing multiple tissue cores of melanomas and benign nevi showed a positive correlation between PLK1 and NOTCH1 in melanoma. Subsequently, utilizing BI 6727 and MK‐0752, a NOTCH inhibitor, this study found a synergistic antiproliferative response of the combined treatment in multiple human melanoma cells. Further, an RNA‐sequencing analysis revealed modulation of several melanoma‐associated genes such as MAPK, PI3K, RAS, Apobec3G, BTK, and FCER1G.
38
Another previous study from our laboratory demonstrated that the expression of Numb, a NOTCH antagonist, was required for PLK1 protein stability and localization to the spindle poles during mitosis in melanoma cells. Dysregulation of Numb expression resulted in the mislocalization of PLK1, contributing to mitotic errors and cancer development.
39
These outcomes were supported by a following study, where PLK1 was found to phosphorylate NUMB at Ser413, and increased migration and invasion of melanoma cells independent of NOTCH activity. Moreover, melanoma TCGA data analysis using high PLK1 with low NUMB or high NOTCH expressions showed a significant decline in the survival of melanoma patients.
40
Overall, these findings warrant further research focusing on the therapeutic targeting of PLK1 and its association with NUMB and NOTCH for melanoma management.
Another important mutation found commonly in melanoma is the mutation in the NRAS gene. NRAS mutations are found in about 20% of melanomas with aggressive disease and poor prognosis. In a collaborative study, we found that PLK1 is overexpressed in melanoma cells with NRAS(Q61) mutations, and a combination of trametinib with BI 6727 in NRAS mutant melanoma cells (WM3629, WM3670, SK‐MEL‐2, MM485, and D04) has synergistic antitumor activity in vitro. In this study, the cell cycle‐related genes CCND1, CDC25A, CHEK2, E2F1, and AurkB were found to be downregulated with stronger induction of pro‐apoptotic signals, such as caspase3/7, with the combined inhibition of MEK and PLK1.
41
All these studies provide evidence that PLK1 expression is correlated with poor prognosis and metastasis in melanoma, suggesting its potential as a biomarker for identifying aggressive melanoma forms. In addition, PLK1 inhibition in combination with BRAF, MEK, or NOTCH inhibitors has synergistic antiproliferative effects, which makes it a potential therapeutic target in melanoma.
Even though PLK2 has not been studied in the context of melanoma, a few studies have shown the role of other members of the PLK family in melanoma. Xu et al. reported deregulation of PLK3 in melanoma cell lines.
42
Later, it was shown that PLK3 expression correlated with resistance to BRAF inhibitors in BRAF‐mutant melanoma cells (A375 and SK‐MEL‐28), and PLK3 suppression increased the efficacy of BRAF inhibitors.
43
Further investigations might help to elucidate the exact mechanistic details correlating PLK3 with melanoma, but the initial results showed a potential for targeting PLK3 for melanoma management.
Another member of the PLK family that has been studied in the context of melanoma is PLK4. Kulukian et al. reported that the elevation of PLK4 in skin epithelial tissue resulted in centrosome amplification, spindle orientation errors, chromosome segregation defects, and multiciliated cells within the epidermis.
44
Similarly, Coelho et al. found PLK4‐mediated hyperproliferation of skin in a p53 null background in a mouse model. PLK4 overexpression in mice showed the loss of differentiated melanocytes and thickening of the epidermis with increased expression of keratin 5, a proliferation marker, in the basal epidermal layer. These effects were mirrored in primary cultures of keratinocytes, setting up the prerequisite for cancer development.
45
Later, in a study from our laboratory, PLK4 was found to be overexpressed in melanoma and contributed to centriole overduplication in melanoma cells. It was observed that the treatment of melanoma cells with the PLK4 inhibitor centrinone B significantly reduced proliferation and induced apoptosis in multiple melanoma cell lines.
46
A recent study correlated the overexpression of PLK4 with melanoma metastasis in tumor specimens of patients undergoing surgical resection. PLK4 was elevated with lymph node metastasis, TNM stage, and poor disease‐free survival in cutaneous melanoma.
47

Much is not known regarding the role of PLK5 in melanoma. A recent study from our laboratory found PLK5 expression to be higher in normal tissues as compared to cancer tissues in multiple cancer types.
48
This study employed RNA‐seq data from TCGA and GTEx databases and found a downregulation of PLK5 in melanoma compared to normal skin tissues. This suggests that PLK5, unlike PLK1, PLK3, and PLK4, might have a tumor suppressor role in melanoma, which needs to be further elucidated using in vitro and in vivo melanoma models.
Taken together, studies show that overexpression of PLK1, PLK3, and PLK4 may promote cancerous transformation of melanocytes and drive their progression. Their inhibition could suppress melanoma proliferation alone and in combination with other targeted therapies. This could be of clinical benefit toward improved first‐and second‐line treatments for resistant, aggressive, and/or metastatic melanoma. On the contrary, the tumor suppressor role of PLK5 should be further explored for a better understanding and its potential in melanoma management. PLKs, predominantly PLK1, have also been associated with non‐melanoma skin cancers, which are discussed in the next section.

Non‐melanoma skin cancers
Non‐melanoma skin cancers, including BCC and SCC, are primarily caused by UV radiation, a well‐established environmental carcinogen. These cancers are closely linked to keratinocyte dysfunction. A limited number of studies have shown a link between PLKs and NMSCs. For example, a study from our lab has shown that PLK1 is overexpressed in both BCC and SCC tumor tissues from patients as well as in SCC cell lines (A253 and A431) compared to normal human epidermal keratinocytes. Additionally, a similar protein expression pattern was found for the downstream targets of PLK1, including Cdk1, Cyclin B1, and Cdc25C.
49
In a separate study, employing integrated mRNA profiling of primary keratinocytes and clinical samples of cutaneous SCC, Watt and colleagues found an upregulation of PLK1 in cSCC samples. It was also shown that inhibition or knockdown of PLK1 led to growth suppression of cSCC cells in vitro with G2/M arrest and no measurable effect on normal keratinocyte growth. There was also a significant reduction in tumor volume in vivo compared to vehicle controls.
50
Another study demonstrated that while inactivation of mitotic checkpoints like PLK1 initially caused polyploidy and differentiation of squamous cells, prolonged cell cycle arrest ultimately triggered apoptosis. This highlights an important role of PLK1 in regulating squamous cell fate, directing them either toward differentiation or apoptosis in response to genetic damage.
51
Zuco et al. have shown the benefit of PLK1 as an adjuvant treatment for resistant SCC. SN38, a topoisomerase inhibitor, is used to treat SCC, but some tumors exhibit resistance. It was shown that modulation of PLK1 expression affects cell sensitivity to SN38, and combining SN38 and BI 2536 could enhance apoptosis in cell lines (CaSki and SiHa) both sensitive and resistant to SN38‐induced apoptotic cell death. This combination also improved antitumor effect in SCC xenografts in mice compared to single‐agent treatments. The effect was reflected as a higher rate of tumor inhibition in mice harboring SCC tumors with intrinsic or acquired resistance to SN38.
52
These findings position PLK1 inhibition as a potential therapeutic strategy for treating NMSCs both as monotherapy and as a part of a combination therapy. However, further research is required to understand and validate the exact role and functional significance of PLKs in NMSCs. Although the role of PLKs is most extensively studied in melanoma and NMSCs, some studies also link their role to other UV‐induced skin cancers, which are discussed below.

Merkel cell carcinoma (MCC)
MCC is a rare and highly aggressive skin malignancy often found on the sun‐exposed areas of the body. It exhibits a high mutation burden associated with a UV‐induced DNA damage signature as observed in other skin cancers. Multiple mutations or amplified cancer genes of possible clinical significance such as RB1, TP53, NOTCH1, cell cycle regulators (CDKN2A, CCNE1, and CDK4), receptor tyrosine kinase FGFR2, and members of the MAPK (HRAS, NF1) and PI3K (PIK3CA, AKT1, and PIK3CG) are observed in MCC tumors.
53
Research has revealed that MCC tumor samples show an upregulation of PLK1 compared to healthy skin.
54
In a preclinical study, PLK1 inhibition by BI 2536 was shown to induce apoptosis and inhibit cell proliferation in MCC cells in vitro. Moreover, BI 2536 was also found to enhance the effects of irradiation and cisplatin, suggesting that PLK1 inhibition could serve as a promising therapeutic approach for MCC both as a monotherapy and in combination with other treatment modalities.
54
However, additional detailed in vitro mechanistic studies and in vivo studies in relevant preclinical models are needed to define the role of PLKs in MCC.

Cutaneous T‐cell lymphoma (CTCL)
CTCL is a rare non‐Hodgkin lymphoma that originates in T lymphocytes. In CTCL, the malignant T cells infiltrate and attack the skin. The role of UV in the pathogenesis of CTCL as an early mutagenic event is controversial.
55
Recently, a study performed a meta‐analysis of whole‐exome sequencing data from CTCL patients. According to the findings, UV‐associated mutational signature 7 (pyrimidine‐pyrimidine photodimers/C>T substitutions) was exclusively found in CTCL and accounted for 23% of the mutational burden in Sezary syndrome and 52% of the mutational burden in Mycosis fungoides, the most common forms of CTCL.
56
Yet, it is not clear whether UV mutations act as an early mutagenic event and trigger CTCL or are the result of the cumulative environmental UV exposure of cutaneous lesions. Interestingly, a collaborative study from our laboratory demonstrated that PLK1 levels were elevated in CTCL, particularly in advanced lesions.
57
Inhibition of PLK1, either through genetic manipulation or small molecule inhibitors, was found to reduce cell growth, viability, and proliferation in CTCL cells in vitro. Additionally, PLK1 inhibition was shown to induce cell cycle arrest and apoptosis in CTCL cells.
58
These findings suggest that targeting PLK1 could be a promising therapeutic strategy for CTCL patients.
Although these studies suggest a potential role and therapeutic significance of PLK1 in CTCL, additional validation and detailed investigations are needed to uncover the contributions of PLK family members in CTCL and to shed further light on the exact mechanisms by which PLK1 and other PLK family members cause CTCL. In the next section, we will discuss in detail how UV regulates PLKs in normal skin and different cancers while trying to interlink these studies to UV‐induced skin cancers.

UV‐MEDIATED REGULATION OF POLO‐LIKE KINASES AND FUTURE PERSPECTIVES
As discussed above, exposure to UV radiation damages DNA, causes mitotic arrest, and makes skin cells vulnerable to mitotic defects. Two critical mechanisms that ensure error‐free replication of genetic material after exposure to UV radiation are DNA damage repair and cell cycle arrest to ensure the integrity of genetic material. However, these mechanisms are dysregulated in cancers, allowing them to proliferate and metastasize.
59
Some studies have shown overexpression of DNA repair genes involved in homologous recombination repair (HRR) in melanomas with metastatic potential
60
,
61
suggesting that maintaining a certain basal level of genetic stability may be beneficial during metastasis.
62
Thus, it is critical to elucidate the exact effects of UV on DNA damage repair and cell cycle‐associated genes and signaling to understand the impact on tumorigenesis and design various personalized therapeutic regimens (Figure 2).
As discussed in earlier sections, being critical regulators of mitosis and the cell cycle, PLKs are known to be dysregulated in UV‐induced skin cancer. PLKs, especially PLK1
63
and PLK3
64
are also known to be involved in mechanisms related to various genotoxic stress and play a critical role in responding to these stressors that contribute to cancer development and progression. Other members of the PLK family may also play crucial roles in responding to DNA damage triggered by various stressors involved in cancer development, primarily by regulating key aspects of cell cycle progression. Although there is insufficient research on how UV modulates different members of the PLK family, a study links PLK1 regulation by UV in skin cancer. This study employed a bioinformatics approach to assess RNA‐Seq datasets based on the National Center for Biotechnology Information‐Gene Expression Omnibus (NCBI‐GEO), comprising 21 UV‐irradiated and 3 non‐irradiated human keratinocytes to find possible predictive biomarkers in skin cancer.
65
The authors found that among the 32 common differentially expressed genes, PLK1 was highly expressed in UV‐irradiated keratinocytes and skin cancer and was significantly associated with poor survival. This showed that PLK1 expression needs to be validated as a clinical biomarker through further investigations in UV‐associated skin cancers.
65
The exact mechanism by which UV causes overexpression of PLK1 remains unknown presently. Owing to the lack of further relevant literature on the role of UV in modulating PLK levels in skin cancers, below, we try to predict the correlation by taking assistance from studies associated with other cancers and normal cells/tissues.
UV radiation has been shown to cause PLK1 inhibition and cell cycle arrest to facilitate DNA damage repair.
66
,
67
PLK1 expression is necessary for cells to re‐enter the cell cycle. Thus, it could be hypothesized that cancer cells use some rescue mechanism as a means of transmitting mitotic defects and continue proliferation after UV exposure, where PLK1 is overexpressed. It was reported that PLK1 is enriched at double‐strand breaks (DSBs) within seconds of UV laser irradiation in osteosarcoma (U2OS) and breast cancer (MCF10A) cells in a PARP‐1 dependent manner, where it lasted only for 10–12 min.
66
Later, Poly (ADP‐ribose) glycohydrolase (PARG) could drive PLK1 dispersal from DNA damage sites, preventing excessive accumulation.
66
PLK1 initial localization was shown to be necessary to phosphorylate and activate RAD51, a protein essential for DNA repair. Moreover, PLK1 activity was also regulated by checkpoint kinase 1 (CHK1), which warrants that damaged or incompletely replicated DNA does not enter mitosis. It phosphorylates PLK1 at T210, which allows PLK1 to activate RAD51. However, CHK1 also inhibits Cdc25 and CDKs, ensuring cell cycle arrest. Overall, the CHK1‐PLK1‐RAD51 axis was found to promote homologous recombination‐mediated repair in UV‐irradiated cancer cells.
66
It was reported that PARP‐1 is upregulated in melanoma
68
and NMSC, especially BCC.
69
Thus, upregulated PARP‐1 could promote excessive localization of PLK1 at DSB sites, promoting the activation of RAD51. Interestingly, overexpression of RAD51, which is regulated by the MAPK signaling pathway, was observed in skin cancers.
70
Thus, there may be a PLK1‐dependent mechanism that could drive this process, as PLK1 is known to activate MAPK.
71
On the other hand, low mRNA expression of CHK1 is significantly associated with good overall survival of melanoma patients.
72
It could be speculated that the UV‐mediated initial transient activation of PLK1 outweighs the later inhibition, allowing cancer cells to use the DNA repair mechanisms to their benefit. Thus, overexpression of CHK1, PLK1, and Rad51 in melanoma suggests a probable role of the CHK1‐PLK1‐RAD51 axis in UV‐induced skin cancers, where cancer cells might steer this UV‐driven axis in a different direction. Whether cancer cells utilize UV to overexpress these targets or UV triggers some other mechanisms that crosstalk with this axis may be resolved by further research.
Similarly, UV‐induced PLK1 inhibition is mediated by ATR in U2OS cells. To relate the UV‐mediated inhibition of PLK1 to ATR, researchers assessed the effects of caffeine on PLK1 activity after treating ATM−/− U2OS cells with UV. Caffeine is known to inhibit the catalytic activity of ATM and ATR kinases. The addition of caffeine completely rescued the inhibitory effect on PLK1, suggesting the role of ATR in regulating UV‐mediated PLK1 activity.
67
Later, a study with 293 T and U2OS cells showed that following UV irradiation, ATR phosphorylates Bora, an activator of PLK1 via Aurora A kinase, resulting in its degradation. This compromises PLK1 activation and contributes to DNA damage‐induced G2 arrest.
73
ATR is known to be downregulated in melanoma
74
and it is speculated that it could lead to overexpression of PLK1 in response to UV. Further, Protein ATLAS data showed upregulation of Bora in skin cancer.
75
Hence, it may be predicted that downregulation of ATR and overexpression of Bora might lead to PLK1 overexpression in skin cancers, thereby forcing cells with DNA damage to replicate with defective DNA, leading to cancer. However, a detailed investigation is required to elucidate the relationship between PLK1, ATR, and Bora in response to UV treatment in skin cancer models.
Another study revealed that PLK1 degradation by SCFFBXW7α in S‐phase and by APC/CCDH1/proteasome in G2‐phase avoids cell proliferation after UV‐induced DNA damage in HEK293 and U2OS cells. This instead initiated a DNA damage repair response
76
to promote precise replication of genetic material. APC/CCDH1 are known to be tumor suppressors in melanoma
77
and thus downregulated in melanoma. Therefore, their downregulation could lead to excessive accumulation of PLK1, leading to the continuation of the cell cycle following UV exposure, forcing cells with DNA damage to replicate with defective DNA, leading to cancer. Additionally, PLK1 was also shown to phosphorylate Primase‐Polymerase (PrimPol) at S538, which is responsible for repriming DNA synthesis downstream of DNA damage to enable replication to resume. Inhibition of PLK1‐dependent phosphorylation of PrimPol induced genomic instability, chromosome breaks, micronuclei, and reduced cell survival of human embryonic kidney cells (HEK293) after treatment with UVC.
78
There is no data on the PLK1‐PrimPol axis in skin cancers. It could be speculated that the overexpression of PLK1 in skin cancers could lead to continued activation of PrimPol, thus forcing cells with defective DNA to replicate, leading to cancer.
Overexpression of PLK1 in UV‐irradiated HEK293 cells was also shown to cause the hyperphosphorylation of Cdc25C, which is required for the G2/M transition. Once activated, Cdc25C acts as a mediator for PLK1 to bind with and dephosphorylate p53 at ser15, leading to its degradation through the Mdm2 pathway. It is suggested that PLK1‐mediated negative regulation of p53 is an important mechanism to rescue cells from UV‐induced mitotic arrest.
79
This pathway, among others, has been previously reviewed in TP53 or RAS‐mutated cancers.
80
This needs to be validated in UV‐induced skin cancer models since Cdc25 phosphatases
81
,
82
and p53
83
are known to be associated with melanoma and non‐melanoma skin cancers. This will provide a better understanding of how UV directly or indirectly interacts with PLK1, Cdc25 phosphatases, and p53 in modulating tumorigenesis in skin cancer.
In addition to PLK1, PLK3 activation occurs after exposure to environmental or genotoxic stresses. PLK3 contributes to the activation of DNA damage checkpoints, which arrest the cell cycle, allowing cells to undergo DNA repair or apoptosis. A study has demonstrated that UV radiation activated PLK3, which in turn interacted with AP‐1 and c‐Jun, which are important to mediate corneal epithelial cell apoptosis after exposure to UV irradiation. Co‐immunoprecipitation experiments showed that PLK3 and c‐Jun directly interacted with each other. PLK3 is co‐localized with c‐Jun in the nuclei of UV‐irradiated corneal epithelial cells, resulting in their apoptosis.
84
,
85
Further analysis showed that UV and hypoxia‐induced PLK3 activity delayed the corneal epithelial wound healing process in the cultured mouse cornea.
86
The above studies showed the role of PLK3 in UV‐irradiated cells to allow DNA repair pathways to prevent transmitting mitotic defects. c‐Jun
87
,
88
is known to be overexpressed in skin cancers, and PLK3 overexpression is known to be a predictor of poor BRAF inhibitor efficacy in melanoma.
43
This suggests a potential existence of a mechanism where PLK3, c‐jun, and UV crosstalk in cancer cells, to evade apoptosis and continue to replicate with defective DNA. Further research is needed to elucidate this pathway for improved insight into the role of PLKs in UV‐induced skin cancers.
Furthermore, PLK4 is known to interact with proteins involved in DNA damage.
89
,
90
,
91
Morettin et al. assessed the effect of heterozygous PLK4 expression after UV exposure in mouse embryonic fibroblasts (MEFs).
92
The level of PLK4 was shown to be decreased in the heterozygous MEFs and increased in the wild‐type post UV exposure. The authors found that even though the basal levels of CHK2, p21, and p53 were higher in the heterozygous MEFs as compared to wild types, UV exposure further increased the levels of CHK2 in both genotypes but could only increase p21 levels in wild‐type cells, whereas p53 did not change in any of the genotypes.
92
Since PLK4 is overexpressed in skin cancers, it could be suggested that UV might have a role in causing that overexpression and bringing in the subsequent changes without altering the apoptotic protein p53 to promote further replication of the damaged DNA. Since there is no data related to this in skin cancers, it would be interesting to study it further to have deeper knowledge about PLK4 overexpression in response to UV radiation in skin cancers.
The immune system plays a critical role in the development and progression of cancer, with various immunomodulatory signals either suppressing tumor growth or promoting more aggressive disease. UV‐related skin malignancies are no exception. The role of UV in immunomodulation is very well documented.
93
Although the specific role of PLKs in immunomodulation within UV‐induced skin cancers remains unclear, recently, a study has highlighted the role of PLKs in immunomodulation.
94
This study utilizing integrated multi‐omics analysis examined the expression patterns of various PLK family members across different cancer types and provided valuable insights into the relationship between PLK expression and immune cell infiltration. These findings suggest that the interplay between UV exposure and PLK‐mediated immunomodulation warrants further investigation, which could ultimately contribute to improved therapeutic strategies and patient outcomes.
Overall, a clear understanding of how UV modulates different members of the PLK family in different UV‐induced skin cancers could open new avenues of research that may be relevant for better‐personalized therapeutic regimens.

CONCLUSIONS
Based on a plethora of evidence, the PLKs have been shown to play a crucial dual role in the cell cycle and the pathophysiology of melanoma and non‐melanoma skin cancers, with a strong etiological connection through UV exposure. It appears that these important kinases play a crucial role in the development and/or progression of skin cancers and need to be extensively investigated in pre‐clinical as well as clinical investigations. While UV radiation is known to cause DNA damage to varying degrees, PLKs are important for homologous recombination for DNA repair and cell cycle progression. Their activity is typically inhibited during excessive and irreparable DNA damage to prevent further progression and promote DNA repair or apoptosis if the damage is irreparable. However, the overexpression of PLKs, especially PLK1, PLK3, and PLK4 in cancer cells, may enable continued cell proliferation despite DNA damage. The detailed molecular mechanisms relating UV to the modulation of PLKs are not well understood, yet the importance of both factors in skin cancer points to potential interactions between these. However, how cancer cells steer the interplay between UV radiation and PLK expression in their favor, and opposite to what is seen in normal cells, to promote cell cycle progression with damaged DNA remains a mystery.
Even though limited evidence has suggested the role of UV in modulating PLKs in skin cancer, some existing studies have focused on the role of UV radiation in regulating PLK1, PLK3, and PLK4 in normal cells and other cancers. Further research may uncover additional insights into how UV influences other members of the PLK family in both normal and cancerous cells and provide a detailed overview of the factors that influence this interplay between UV and PLKs in UV‐induced skin cancers. PLK2 and PLK5 are known to be tumor suppressors. Although no study has linked UV to the modulation of PLK2 and PLK5, their role as a tumor suppressors in UV‐induced skin cancers warrants an in‐depth analysis of the mechanisms interlinking these PLKs to UV, which may lead to a downregulation of these PLKs in cancer cells following various known or undiscovered pathways.
Taken together, research on how UV modulates different members of the PLK family in UV‐associated skin cancers could provide greater insight into the tumorigenesis of skin cancers. This would lead to new knowledge and may also open new avenues for improved treatment strategies using PLK‐targeted therapies either as monotherapy or as a part of a combination therapy for better clinical outcomes. Certain PLK1 inhibitors, such as volasertib, onvansertib, and PLK4 inhibitor, CFI‐400945, are being tested in clinical trials for the treatment of certain cancers. Hence, further research studying the interplay between UV radiation and PLK family members in skin cancers is needed.

AUTHOR CONTRIBUTIONS
Conceptualization, TJ, GC, and NA. Writing—original draft preparation, TJ and DM. Writing—review and editing, TJ, DM, GC, and NA. Tables and figures, TJ and DM. Supervision, NA. Project administration, NA. All authors contributed to the article and approved the submitted version.

CONFLICT OF INTEREST STATEMENT
The authors declare no potential conflict of interest.