Histone and DNA Methylation as Epigenetic Regulators of DNA Damage Repair in Gastric Cancer and Emerging Therapeutic Opportunities

Simple Summary Histone and DNA methylations are widely studied epigenetic marks in gastric cancer. Methylation is involved in DNA damage repair (DDR) and can also regulate non-histone DDR proteins, thereby orchestrating DNA repair processes. Homologous recombination is the main pathway involved in the repair of double-strand breaks. Defects in the homologous recombination DNA repair system can cause homologous recombination deficiency (HRD). In this context, targeting DDR pathways has emerged as a promising cancer treatment strategy, with DDR inhibitors (especially PARP inhibitors) showing clinical success. In this review, we will discuss the alterations detected in histone and DNA methylation in gastric cancer and describe how these epigenetic processes affect DDR in gastric carcinogenesis. Moreover, we will dissect the applications of DDR inhibitors in the context of HRD and their promising role in gastric cancer treatment.Abstract Gastric cancer (GC), one of the most common malignancies worldwide, is a heterogeneous disease developing from the accumulation of genetic and epigenetic changes. One of the most critical epigenetic alterations in GC is DNA and histone methylation, which affects multiple processes in the cell nucleus, including gene expression and DNA damage repair (DDR). Indeed, the aberrant expression of histone methyltransferases and demethylases influences chromatin accessibility to the DNA repair machinery; moreover, overexpression of DNA methyltransferases results in promoter hypermethylation, which can suppress the transcription of genes involved in DNA repair. Several DDR mechanisms have been recognized so far, with homologous recombination (HR) being the main pathway involved in the repair of double-strand breaks. An increasing number of defective HR genes are emerging in GC, resulting in the identification of important determinants of therapeutic response to DDR inhibitors. This review describes how both histone and DNA methylation affect DDR in the context of GC and discusses how alterations in DDR can help identify new molecular targets to devise more effective therapeutic strategies for GC, with a particular focus on HR-deficient tumors.