Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator.
High expression of metastasis-associated protein 1 co-regulator (MTA1), a component of the nuclear remodelling and histone deacetylase complex, has been associated with human tumours. However, the precise role of MTA1 in tumorigenesis remains unknown. In this study, we show that induced levels of MTA1 are sufficient to transform Rat1 fibroblasts and that the transforming potential of MTA1 is dependent on its acetylation at Lys626. Underlying mechanisms of MTA1-mediated transformation include activation of the Ras-Raf pathway by MTA1 but not by acetylation-inactive MTA1; this was due to the repression of Galphai2 transcription, which negatively influences Ras activation. We observed that acetylated MTA1-histone deacetylase (HDAC) interaction was required for the recruitment of the MTA1-HDAC complex to the Galphai2 regulatory element and consequently for the repression of Galphai2 transcription and expression leading to activation of the Ras-Raf pathway. The findings presented in this study provide for the first time--to the best of our knowledge--evidence of acetylation-dependent oncogenic activity of a cancer-relevant gene product.
Ohshiro
Kazufumi
K
Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, 2300 I Street Northwest, Washington, District of Columbia 20037, USA.
Rayala
Suresh K
SK
Wigerup
Caroline
C
Pakala
Suresh B
SB
Natha
Reddy S Divijendra
RS
Gururaj
Anupama E
AE
Molli
Poonam R
PR
Månsson
Sofie Svensson
SS
Ramezani
Ali
A
Hawley
Robert G
RG
Landberg
Goran
G
Lee
Norman H
NH
Kumar
Rakesh
R
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009857:Oncogenes; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases; D051960:GTP-Binding Protein alpha Subunit, Gi2; D018631:ras Proteins; D008239:Lysine