Discovery of KMT5A repressed miR-99b cluster with potential to restore chemotherapy sensitivity in gastric cancer by regulating mitochondrial complex II and affecting OXPHOS.

Gastric cancer remains a formidable global health challenge, with drug resistance being a primary contributor to its high mortality rates. Therefore, understanding the mechanisms driving drug resistance is crucial for developing more effective therapeutic interventions. Utilizing high content screening technology, we identified let-7e-5p and miR-125a-5p as the key regulators of drug resistance in GC, both being members of the miR-99b cluster. Findings from GC cells, organoids and PDX models demonstrated that overexpression of the miR-99b cluster sensitized GC to cisplatin, likely through its inhibitory effects on mitochondrial respiratory function, particularly OXPHOS. We further demonstrated that multiple components, especially SDHC subunit of respiratory complex II, were regulated by miR-99b cluster and played critical roles in GC chemoresistance. Then, through a comprehensive screen of epigenetic compounds, we identified KMT5A as a key upstream repressor of the miR-99b cluster in GC, which reinforces the H4K20me1 modification within the miR-99b cluster region. Moreover, elevated KMT5A expression and decreased miR-125a-5p expression indicated both poorer prognosis and chemo-resistance in patients with GC. This study highlights the multifaceted roles of the miR-99b cluster in GC and offers novel perspectives for the development of innovative therapeutics aimed at overcoming chemoresistance and enhancing treatment efficacy for GC patients.