G9a: An Emerging Epigenetic Target for Melanoma Therapy

Abstract

Epigenetic regulation is a crucial component of DNA maintenance and cellular identity. As our understanding of the vast array of proteins that contribute to chromatin accessibility has advanced, the role of epigenetic remodelers in disease has become more apparent. G9a is a histone methyltransferase that contributes to immune cell differentiation and function, neuronal development, and has been implicated in diseases, including cancer. In melanoma, recurrent mutations and amplifications of G9a have led to its identification as a therapeutic target. The pathways that are regulated by G9a provide an insight into relevant biomarkers for patient stratification. Future work is aided by the breadth of literature on G9a function during normal differentiation and development, along with similarities to EZH2, another histone methyltransferase that forms a synthetic lethal relationship with members of the SWI/SNF complex in certain cancers. Here, we review the literature on G9a, its role in melanoma, and lessons from EZH2 inhibitor studies.

PROTACable Is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning To Automate the De Novo Design of PROTACs

“…The G9a protein, also known as euchromatic histone-lysine N-methyltransferase 2 (EHMT2), plays a crucial role in histone methylation, influencing gene expression and cellular differentiation. 75 Targeting G9a is advantageous in therapeutic strategies, particularly in cancer treatment, due to its significant involvement in tumor growth and metastasis, as evidenced in various studies highlighting its overexpression in cancers like melanoma. 75 In order to showcase the applicability of the PROTACable pipeline, the G9A inhibitor UNC0642 (IC 50 1−20 μM in T24, J82, and 5637 cells 76 ) (Figure 6A) was proposed for developing new PROTACs.…”

“…75 Targeting G9a is advantageous in therapeutic strategies, particularly in cancer treatment, due to its significant involvement in tumor growth and metastasis, as evidenced in various studies highlighting its overexpression in cancers like melanoma. 75 In order to showcase the applicability of the PROTACable pipeline, the G9A inhibitor UNC0642 (IC 50 1−20 μM in T24, J82, and 5637 cells 76 ) (Figure 6A) was proposed for developing new PROTACs. The solved crystal structure of a G9A structure with inhibitor UNC0638 77 was used to validate the docking pose of the closely related analog SMI UNC0642 after Stage I of PROTACable.…”

EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway

“…Through the methylation of H3K9, EHMT2 can have a wide range of effects on many signal pathways, which not only depend on the tumor's own development and genetic background, but also change tumor and microenvironment cells 38 . Elevated expression of EHMT2 has been observed in a variety of cancers and linked to drug resistance and metastasis 29 .…”

PROTACable is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning to Automate the De Novo Design of PROTACs

“…The G9a protein, also known as euchromatic histone-lysine N-methyltransferase 2 (EHMT2), plays a crucial role in histone methylation, influencing gene expression and cellular differentiation 57 . Targeting G9a is advantageous in therapeutic strategies, particularly in cancer treatment, due to its significant involvement in tumor growth and metastasis, as evidenced in various studies highlighting its overexpression in cancers like melanoma 57 . In order to showcase the applicability of PROTACable pipeline, the G9A inhibitor UNC0642 (IC50 1−20 μM in T24, J82, and 5637 cells 58 ) (Figure 6A) was proposed for developing new PROTACs.…”