GATA Transcription Factors and Cancer

Abstract

It has been almost a quarter century since it was first appreciated that a class of oncogenes contained in rapidly transforming avian retroviruses encoded DNA-binding transcription factors. As with other oncogenes, genetic recombination with the viral genome led to their overexpression or functional alteration. In the years that followed, alterations of numerous transcription factors were shown to be causatively involved in various cancers in human patients and model organisms. Depending on their normal cellular functions, these factors were subsequently categorized as proto-oncogenes or tumor suppressor genes. This review focuses on the role of GATA transcription factors in carcinogenesis. GATA factors are zinc finger DNA binding proteins that control the development of diverse tissues by activating or repressing transcription. GATA factors thus coordinate cellular maturation with proliferation arrest and cell survival. Therefore, a role of this family of genes in human cancers is not surprising. Prominent examples include structural mutations in GATA1 that are found in almost all megakaryoblastic leukemias in patients with Down syndrome; loss of GATA3 expression in aggressive, dedifferentiated breast cancers; and silencing of GATA4 and GATA5 expression in colorectal and lung cancers. Here, we discuss possible mechanisms of carcinogenesis vis-à-vis the normal functions of GATA factors as they pertain to human patients and mouse models of cancer.

MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma

“…In fact, GATA4 is a lineage selector gene, and its upregulation suggests dedifferentiation and loss of organ identity, which is in line with the theory that the metastatic process is a recapitulation of ontogeny (5). GATA4 promotes the expression of the antiapoptotic factor Bcl2 and cyclin D2 (17), increases proliferation and migration capacities in colorectal cancer (18), and its altered expression is correlated with a broad range of tumors emerging from gastrointestinal tract, lungs, ovaries, brain, and with poor prognosis in ovarian granulose cell tumors (19).…”

“…This protein may bind to the hypomethylated region of the GATA4 promoter, and thus regulate its expression, or even act as a partner in metastasis development. Although controversial, hypermethylation of GATA4 in lung cancer has been reported (18,26). A study from Guo and colleagues on the methylation of GATA genes in lung cancer used several lung cancer cell lines revealing GATA4 silencing by hypermethylation in most of the tested cells, including A549 (26).…”

Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin

“…185,186 Together with placental S100 (S100P), it was recently reported as a useful immunohistochemical marker for the detection of urothelial carcinoma and ovarian Brenner tumors. 69,70 Low GATA3 expression has also been suggested to correlate with poor prognosis in breast cancer.…”

GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma

“…GATA3 is one member of the zinc-finger transcription family involved in the regulation, speciation, differentiation and proliferation of cells during development of multiple organs, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] including the nervous 13 and urogenital system. 3 Amongst tumors, it labels urothelial carcinoma, collecting duct carcinoma of the kidney, breast carcinoma, lymphoma and, uncommonly, endometrial carcinoma.…”