Mechanism of MTA1 protein overexpression-linked invasion: MTA1 regulation of hyaluronan-mediated motility receptor (HMMR) expression and function.
Even though the hyaluronan-mediated motility receptor (HMMR), a cell surface oncogenic protein, is widely up-regulated in human cancers and correlates well with cell motility and invasion, the underlying molecular and nature of its putative upstream regulation remain unknown. Here, we found for the first time that MTA1 (metastatic tumor antigen 1), a master chromatin modifier, regulates the expression of HMMR and, consequently, its function in breast cancer cell motility and invasiveness. We recognized a positive correlation between the levels of MTA1 and HMMR in human cancer. Furthermore, MTA1 is required for optimal expression of HMMR. The underlying mechanism includes interaction of the MTA1·RNA polymerase II·c-Jun coactivator complex with the HMMR promoter to stimulates its transcription. Accordingly, selective siRNA-mediated knockdown of HMMR in breast cancer cells substantially reduces the invasion and migration of cells. These findings reveal a regulatory role for MTA1 as an upstream coactivator of HMMR expression and resulting biological phenotypes.
Integrated Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India.
Deivendran
D
Sankaran
Suresh B
SB
Pakala
Vasudha S
VS
Nair
Divijendra Natha Reddy
DN
Sirigiri
Dinesh
D
Cyanam
Ngoc-Han
NH
Ha
Da-Qiang
DQ
Li
T R
TR
Santhoshkumar
M Radhakrishna
MR
Pillai
Rakesh
R
Kumar
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D012319:RNA Polymerase II / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000235:genetics
D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; C098946:hyaluronan-mediated motility receptor; D048031:JNK Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II; D006655:Histone Deacetylases