G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a particularly aggressive cancer with poor prognosis, largely due to lymph node metastasis and local recurrence. Emerging evidence suggests that epithelial-to-mesenchymal transition (EMT) is important for cancer metastasis, and correlated with increased cancer stem cells (CSCs) characteristics. However, the mechanisms underlying metastasis to lymph nodes in HNSCC is poorly defined. In this study, we show that E-cadherin repression correlates with cancer metastasis and poor prognosis in HNSCC. We found that G9a, a histone methyltransferase, interacts with Snail and mediates Snail-induced transcriptional repression of E-cadherin and EMT, through methylation of histone H3 lysine-9 (H3K9). Moreover, G9a is required for both lymph node-related metastasis and TGF-β-induced EMT in HNSCC cells since knockdown of G9a reversed EMT, inhibited cell migration and tumorsphere formation, and suppressed the expression of CSC markers. Our study demonstrates that the G9a protein is essential for the induction of EMT and CSC-like properties in HNSCC. Thus, targeting the G9a-Snail axis may represent a novel strategy for treatment of metastatic HNSCC.

Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

“…We observed that our established cisplatin-resistant HNSCC cells with increased G9a also possess more stemness properties than their parental cells. Recent studies have found that G9a is essential for maintaining cancer stemness through epigenetic regulation, especially in H3K9me2 (9,49). Therefore, we suspect that G9a-mediated epigenetic machinery not only contributes to drug resistance, but also induces or maintains stem-like phenotypes in drug-resistant cells.…”

“…5,6). In several cancers including HNSCC, G9a expression and enzymatic activity are positively correlated with malignant behavior, such as cancer growth, survival, cell mobility, and epithelial-mesenchymal transition (7)(8)(9)(10). Although the action of G9a in cancer progression has been widely documented, its role in chemotherapeutic resistance remains unclear.…”

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

“…Nowadays, several studies provide strong evidence for the existence of a cellular subpopulation with stem-like traits also in NSCLC [20,22,23], where the presence of these cells predicts a worse prognosis for patients [24]. Currently, the development of new treatment strategies that target CSCs, as well as the identification of new druggable pathways, are the main goals of anti-cancer therapy [25][26][27][28][29][30][31][32][33][34]. Commercially available established cancer cell lines cannot account for the genetic diversity among patients or for the heterogeneity of tumor cells.…”

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

“…Indeed, overexpression and gene amplification of G9a were observed in a number of human cancers, but GLP was observed in only a few cases (54). In addition, G9a, not GLP, was often evaluated as a marker of aggressive cancers (55)(56)(57). For these reasons, we performed an in vivo metastasis experiment using ovarian cancer cell lines overexpressing G9a or its NQ-mutant, and successfully showed the involvement of the FIH/G9a axis in cancer metastasis (Fig.…”