Translating G9a epigenetics' role: From cell machinery to cancer therapy.

Aberrant epigenetic patterns, and specifically, abnormal histone methylation accumulation, are known hallmarks of cancer development and progression. Considering this mechanism, the histone methyltransferase G9a has emerged as a key player influencing several oncogenic signaling pathways. The targeted histone residue dictates its primary enzymatic role on tumor suppressor gene silencing. Nonetheless, under similar cancer-related contexts, this enzyme can also methylate non-histone proteins, mainly related to oncogenic signaling. With this, G9a further promotes a mesenchymal and stem-cell-like phenotype, ultimately driving drug resistance acquisition. However, even though G9a has been reported as an oncogenic driver in several tumor models, as is the case with prostate cancer (PCa), the specific molecular networks altered by its hyperactivation need further investigation. In this review, we provide a comprehensive overview of the epigenetic role of G9a in cancer, and specifically, in PCa, highlighting the current research status of G9a-targeted therapies. From the literature, we can conclude that while significant progress has been made in characterizing the molecular mechanisms regulated by G9a in cancer, elucidating its context-specific roles across tumor types remains a key challenge to identify potential tumor vulnerabilities. This knowledge could facilitate the rational design of targeted treatment strategies incorporating G9a inhibitors, either as monotherapy or in combination with existing standard-of-care regimens, with the potential to enhance clinical outcomes.