HSF1 promotes malignant phenotype in colorectal cancer via super-enhancer-driven lncRNA EXOSC10-AS1 and targeting HSF1 confers sensitivity to poly (ADP-ribose) polymerase inhibitor Niraparib.

Super-enhancers exert a versatile role in tumor development by recruiting distinct transcription factors. This research aimed to further reveal the relevance between super-enhancers and transcription factor HSF1, the underlying regulatory mechanisms of HSF1, and the potential clinical application value of HSF1 in colorectal cancer (CRC). Following molecular docking, molecular dynamics simulation, and in vitro and in vivo assays, we identified that pharmacological inhibition of HSF1 by the specific inhibitor KRIBB11 attenuated CRC formation, highlighting the therapeutic potential of targeting HSF1 in this malignancy. Using chromatin immunoprecipitation sequencing, we profiled HSF1 enrichment and identified a strong correlation between HSF1 and super-enhancers in CRC. Through lncRNA microarray technology, we screened a new super-enhancer-driven lncRNA EXOSC10-AS1, whose expression was up to HSF1 activity. The roles of EXOSC10-AS1 were further dissected by quantitative PCR, fluorescence in situ hybridization, CCK8 and colony formation assays, RNA sequencing, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The results demonstrated that EXOSC10-AS1 was beneficial for cell proliferation by promoting ORM1 expression, which activated the PI3K/AKT/mTOR/P70S6K signaling pathway. Notably, the HSF1/EXOSC10-AS1/ORM1 axis showed a compensatory elevation when using poly (ADP-ribose) polymerase (PARP) inhibitor-Niraparib (MK-4827) in CRC cells. Finally, inhibiting HSF1 reinforced the anticancer effect of MK-4827 both in vitro and in vivo. In sum, HSF1 accelerates super-enhancer-driven lncRNA EXOSC10-AS1 transcription to facilitate ORM1 expression, leading to PI3K/AKT/mTOR/P70S6K signal activation. Targeting HSF1 is sensitive to synergistic combination PARP inhibitor treatment in CRC. Therefore, our study provides a new approach to synergize PARP inhibitor for CRC therapy.