Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Abstract

Malignant melanoma is a type of very dangerous skin cancer. Histone modifiers usually become dysregulated during the process of carcinoma development, thus there is potential for a histone modifier inhibitor as a useful drug for cancer therapy. There is a multitude of evidence regarding the role of G9a, a histone methyltransferase (HMTase), in tumorigenesis. In this study, we first showed that G9a was significantly upregulated in melanoma patients. Using the TCGA database, we found a significantly higher expression of G9a in primary melanoma samples (n = 461) compared to normal skin samples (n = 551). Next, we knocked down G9a in human M14 and A375 melanoma cell lines in vitro via small interfering RNA (siRNA). This resulted in a significant decrease in cell viability, migration and invasion, and an increase in cell apoptosis. UNC0642 is a small molecule inhibitor of G9a that demonstrates minimal cell toxicity and good in vivo pharmacokinetic characteristics. We investigated the role of UNC0642 in melanoma cells, and detected its anti-cancer effects in vitro and in vivo. Next, we treated cells with UNC0642, and observed a significant decrease in cell viability in M14 and A375 cell lines. Furthermore, treatment with UNC0642 resulted in increased apoptosis. In immunocompetent mice bearing A375 engrafts, treatment with UNC0642 inhibited tumor growth. Results of Western blot analysis revealed that administration of UNC0642 or silencing of G9a expression by siRNA reduced Notch1 expression significantly and decreased the level of Hes1 in A375. All in all, the data from our study demonstrates potential of G9a as a therapeutic target in the treatment of melanoma.

DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

“…In addition, CM-272 is a potent dual inhibitor of G9a (a type of histone methyltransferase) and DNMTs for the treatment of hematological malignancies [ 119 ]. G9a is responsible for methylating lysine 9 of histone 3 (H3K9), and overexpression of G9a leads to increased tumor progression in some tumors [ 120 , 121 ]. It is involved in the transcriptional repression of the tumor suppressor gene PTEN , and upregulation of the G9a gene and downregulation of the PTEN gene can predict poor overall survival [ 122 ].…”

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

“…It has been observed that the expression of G9a is upregulated in a number of cancers, including aggressive lung cancer, multiple myeloma, aggressive ovarian carcinoma, brain cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and malignant melanoma (Wozniak et al, 2007;Gao et al, 2013;Hua et al, 2014;Lehnertz et al, 2014;Hu et al, 2019;Dang et al, 2020). Higher G9a expression levels have often been associated with poor prognosis (Chen et al, 2010;Ke et al, 2014;Zhang et al, 2019).…”

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

“…Conversely, G9a inhibition downregulated HES1 in both protein level and TF activity in GSC, which has been reported to promote EMT and cell migration [90]. The underlying regulation can be explained by the function of G9a as a coactivator, since it has been reported that G9a activates the Notch signaling pathway by regulating Notch1 and Hes1 in cancer progression of melanoma[91]. Another possibility is that G9a might promote AKT activity which in turn upregulates HES1[61, 92].…”