G9a
Histone methyltransferases (HMTs) govern histone methylation and, by reshaping chromatin, direct transcription. Their aberrant activation is documented across many cancers. Among them, G9a (EHMT2) installs methylation on lysine 9 of histone H3 (H3K9); its dysregulation is tightly linked to tumor initiation and progression.G9a chiefly generates H3K9me2, a mark associated with transcriptional silencing and heterochromatin. G9a deletion in mice causes embryonic lethality, underscoring its developmental importance. Elevated G9a correlates with poor prognosis and sustains self-renewal of cancer stem cells. By silencing tumor-suppressor genes through H3K9me2, G9a can accelerate proliferation.Together with GLP, G9a methylates H3K9 to silence transcription and build heterochromatin, while also controlling embryogenesis, DNA-damage responses, immune-cell differentiation, stem-cell fate, and energy metabolism.Beyond H3K9me1/me2, G9a methylates non-histone substrates such as p53 and HIF-1. It further represses transcription by recruiting complexes containing myogenin, p21, or JAK-2. Its mis-expression disrupts development, promotes tumorigenesis, and predicts adverse outcomes. During DNA damage, G9a modulates the p53 pathway to influence apoptosis. G9a is up-regulated and linked to aggressiveness, chemo-resistance, and reduced survival in gastric, breast, hepatocellular, and colorectal cancers, positioning it as both an epigenetic master regulator and a therapeutic target.CtBP1 and CtBP2 share high sequence and functional homology. They recognize PXDLS and non-PXDLS motifs, nucleate multiprotein complexes, and recruit chromatin modifiers to repress or activate transcription. CtBP2/1 partners with DNA-binding proteins (e.g., ZEB1), histone modifiers (HDAC1/2, G9a, Eu-HMTase1), chromodomain proteins (HPC2, CDYL), and CoREST components. By repressing p53 and its targets, CtBP2/1 controls metabolism and proliferation. Multiple studies implicate CtBP2/1 in cancer onset, metastasis, and poor prognosis. Elucidating how CtBP2/1 drives malignancy is therefore essential for advancing epigenetic cancer therapy and improving patient outcomes.