Upstream determinants of estrogen receptor-alpha regulation of metastatic tumor antigen 3 pathway.
Although recent studies have shown a role of estrogen receptor-alpha (ER) in the regulation of epithelial-to-mesenchymal transition via MTA3, the role of upstream determinants of ER regulation of MTA3 and the underlying molecular mechanism remains unknown. Here we show that MTA3 gene regulation by ER is influenced by dynamic changes in levels of nuclear coregulators. MTA3 promoter has a functional ER element half-site with which MTA1 and HDACs interact under basal conditions. Upon estrogen stimulation, these corepressors are derecruited with concomitant recruitment of ER, leading to increased MTA3 transcription and expression. Genetic inactivation of MTA1 pathway promotes the ability of ER to up-regulate MTA3 expression, whereas knockdown of ER enhances MTA1 association with MTA3 gene. Modulation of ER functions, by corepressors (i.e. MTA1 and MTA1s) or coactivators (i.e. AIB1 and PELP1/MNAR), alters ER recruitment to MTA3 chromatin, MTA3 transcription, and expression of downstream epithelial-to-mesenchymal transition components. These studies provide novel insights into the transregulation of the MTA3 gene and reveal novel roles of upstream determinants in modifying the outcome of MTA3 axis and cell differentiation.
Mishra
Sandip K
SK
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Talukder
Amjad H
AH
Gururaj
Anupama E
AE
Yang
Zhibo
Z
Singh
Rajesh R
RR
Mahoney
My G
MG
Francí
Clara
C
Vadlamudi
Ratna K
RK
Kumar
Rakesh
R
D001665:Binding Sites; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000378:metabolism*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators; D014158:Transcription, Genetic; D015854:Up-Regulation
D002843:Chromatin; D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D004967:Estrogens; C486657:MTA3 protein, human; C089320:MTA1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases