RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis

J Huang; A Stewart; B Maity; J Hagen; R L Fagan; J Yang; D E Quelle; C Brenner; R A Fisher

doi:10.1038/onc.2013.324

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RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis

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RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis

J Huang, A Stewart, B Maity, J Hagen, R L Fagan, J Yang, D E Quelle, C Brenner and R A Fisher

Oncogene, Vol.33(27), pp.3604-3611

07/03/2014

DOI: 10.1038/onc.2013.324

PMCID: PMC4232305

PMID: 23995786

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Abstract

The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.

Cell Line

Signal Transduction

DNA (Cytosine-5-)-Methyltransferase 1

Humans

DNA (Cytosine-5-)-Methyltransferases - metabolism

Animals

Cell Transformation, Neoplastic

Proteolysis

Histone Acetyltransferases - metabolism

Cell Line, Tumor

RGS Proteins - metabolism

Trans-Activators - metabolism

Mice

Lysine Acetyltransferase 5

Apoptosis

Proto-Oncogene Proteins p21(ras) - metabolism

Details

Title: Subtitle: RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis
Creators: J Huang - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
A Stewart - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
B Maity - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
J Hagen - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
R L Fagan - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
J Yang - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
D E Quelle - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
C Brenner - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
R A Fisher - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Oncogene, Vol.33(27), pp.3604-3611
DOI: 10.1038/onc.2013.324
PMID: 23995786
PMCID: PMC4232305
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Publisher: England
Grant note: CA075954 / NCI NIH HHS CA161882 / NCI NIH HHS R01 CA090367 / NCI NIH HHS HHSN261200433000C / PHS HHS CA090367 / NCI NIH HHS R01 CA161882 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 07/03/2014
Academic Unit: Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788433102771

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