MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma

Abstract

Human lung cancer is a disease with high incidence and accounts for most cancer-related deaths in both men and women. Metastasis is a common event in non-small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis from NSCLC, but the mechanism underlying this switch remained to be identified. Here, we focus on GATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of the MYC-associated zinc finger protein (MAZ) from the GATA4 promoter, which leads to GATA4 expression. Histone modification analysis of the GATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy.

GATA4 immunolocalization in breast carcinoma as a potent prognostic predictor

“…In contrast, Barbosa et al . showed that GATA4 mRNA expression was more abundant in metastasizing adrenocortical tumors than non‐metastasizing tumors and very recently Castro et al . demonstrated that GATA4 was necessary for MYC‐induced metastasis in lung adenocarcinoma.…”

“…In addition, Hua et al (46) reported that the GATA4 gene was activated by HER2, whereas HER2 expression was repressed by GATA4 through its direct binding to the regulatory sequences, indicating a direct functional link between GATA4 and HER2 in breast carcinoma. In contrast, Barbosa et al (47) showed that GATA4 mRNA expression was more abundant in metastasizing adrenocortical tumors than non-metastasizing tumors and very recently Castro et al (35) demonstrated that GATA4 was necessary for MYC-induced metastasis in lung adenocarcinoma. Therefore, it is suggested that GATA4 is involved in oncogene-dependent signaling including HER2 in the development of distant metastasis with breast carcinoma.…”

“…(32) In contrast, GATA4 was frequently expressed in neuroblastoma, but was negative in the developing nervous system. (33) GATA4 promoter demethylation was induced by several factors including the mitogen-activated protein kinase pathway (34) and MYC, (35) and GATA4 promoted initiation of adrenocortical neoplasms in mice. (36) The results in the present study suggest that GATA4 is overexpressed in breast carcinoma compared with normal breast tissues and plays important roles in breast carcinoma from an early stage.…”

Distinct Expression and Prognostic Values of GATA Transcription Factor Family in Human Ovarian Cancer.

“…Thus, GATA4 and GATA5 is currently considered potential tumour suppressors, however, GATA6 can be used as a potential oncogene [6]. Altered expression of GATA4, GATA5, and GATA6 are associated with abroad range of tumours emerging from the gastrointestinal tract [50], lungs [51] and brain [52]. Moreover, some studies reported that methylation in the GATA4 and GATA6 promoter region could play an important role in ovarian carcinogenesis, elevated GATA4 and lower GATA6 mRNA levels are associated with better prognosis in ovarian tumours [21,22,25].…”

GATA4 is highly expressed in childhood acute lymphoblastic leukemia, promotes cell proliferation and inhibits apoptosis by activating BCL2 and MDM2

“…The GATA family of transcription factors serve various roles in the process of cell proliferation and differentiation (29,30). The expression of GATA4 has been extensively studied in a number of carcinomas (31)(32)(33)(34). Previous studies have reported that the expression of GATA4 was low in several cancers, including colorectal cancer, adrenocortical tumors, epithelial ovarian cancer and hepatocellular carcinoma, which suggested that GATA4 may serve as a tumor suppressor (35).…”