E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases

RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of...

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Veröffentlicht in:The Journal of biological chemistry 2018-04, Vol.293 (15), p.5624-5635
Hauptverfasser: Karthik, Isai Pratha, Desai, Pavitra, Sukumar, Sudarkodi, Dimitrijevic, Aleksandra, Rajalingam, Krishnaraj, Mahalingam, Sundarasamy
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container_issue 15
container_start_page 5624
container_title The Journal of biological chemistry
container_volume 293
creator Karthik, Isai Pratha
Desai, Pavitra
Sukumar, Sudarkodi
Dimitrijevic, Aleksandra
Rajalingam, Krishnaraj
Mahalingam, Sundarasamy
description RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of the classical enzymatic RAS effectors. Whereas most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its down-regulation remains unknown. Here, we unveil E4BP4 as a critical transcriptional modulator repressing RASSF8 expression through histone methyltransferases, G9a and SUV39H1. In line with these observations, we noticed a negative correlation of RASSF8 and E4BP4 expression in primary breast tumor samples. In addition, our data provide evidence that E4BP4 attenuates RASSF8-mediated anti-proliferation and apoptosis, shedding mechanistic insights into RASSF8 down-regulation in breast cancers. Collectively, our study provides a better understanding on the epigenetic regulation of RASSF8 function and implicates the development of better treatment strategies.
doi_str_mv 10.1074/jbc.RA117.000623
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subjects apoptosis
Basic-Leucine Zipper Transcription Factors - genetics
Basic-Leucine Zipper Transcription Factors - metabolism
breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
cell proliferation
E4BP4
Epigenesis, Genetic
Female
G9a
Gene Expression Regulation, Neoplastic
HEK293 Cells
Histocompatibility Antigens - genetics
Histocompatibility Antigens - metabolism
histone methylation
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - metabolism
Humans
MCF-7 Cells
Methyltransferases - genetics
Methyltransferases - metabolism
Molecular Bases of Disease
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Ras protein
RASSF8
Repressor Proteins - genetics
Repressor Proteins - metabolism
SUV39H1
tumor cell biology
tumor suppressor gene
Tumor Suppressor Proteins - biosynthesis
Tumor Suppressor Proteins - genetics
title E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases
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