RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by promoting p53 activation and DNMT1 downregulation

Jianqi Yang; Lance T Platt; Biswanath Maity; Katelin E Ahlers; Zili Luo; Zhibo Lin; Bandana Chakravarti; Stella-Rita Ibeawuchi; Ryan W Askeland; Jolanta Bondaruk; Bogdan A Czerniak; Rory A Fisher

doi:10.18632/oncotarget.12473

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RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by promoting p53 activation and DNMT1 downregulation

Journal article

Open access

Peer reviewed

RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by promoting p53 activation and DNMT1 downregulation

Jianqi Yang, Lance T Platt, Biswanath Maity, Katelin E Ahlers, Zili Luo, Zhibo Lin, Bandana Chakravarti, Stella-Rita Ibeawuchi, Ryan W Askeland, Jolanta Bondaruk, …

Oncotarget, Vol.7(43), pp.69159-69172

10/25/2016

DOI: 10.18632/oncotarget.12473

PMCID: PMC5342467

PMID: 27713144

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Abstract

Urinary bladder cancer (UBC) is largely caused by exposure to toxic chemicals including those in cigarette smoke (i.e. BBN). An activating SNP in RGS6 is associated with a pronounced reduction in UBC risk, especially among smokers. However, the mechanism underlying this reduction remains unknown. Here we demonstrate that RGS6 is robustly expressed in human urothelium, where urothelial cell carcinoma originates, and is downregulated in human UBC. Utilizing RGS6-/- mice we interrogated a possible role for RGS6 as a tumor suppressor using the BBN-induced bladder carcinogenesis model that closely recapitulates human disease. As in humans, RGS6 is robustly expressed in mouse urothelium. RGS6 loss dramatically accelerates BBN-induced bladder carcinogenesis, with RGS6-/- mice consistently displaying more advanced pathological lesions than RGS6+/+ mice. Furthermore, BBN treatment promotes urothelial RGS6 mRNA and protein downregulation. RGS6 loss impairs p53 activation and promotes aberrant accumulation of oncogenic protein DNMT1 in urothelium. Tumor suppressor RASSF1A, a DNMT1-regulated gene, is also silenced, likely via methylation of its promoter during BBN exposure. We hypothesize that this BBN-induced RGS6 loss represents a critical hit in UBC as it irrevocably impairs the anti-proliferative actions of the ATM/p53 and RASSF1A pathways. Consistent with these findings, RGS6-/- mice treated with CP-31398, a p53-stablizing agent, and/or 5-Aza, a DNMT1 inhibitor, are protected from BBN-induced tumorigenesis. Together, our data identify RGS6 as a master tumor suppressor modulating two critical signaling pathways that are often dysregulated in UBC; therefore, RGS6 represents a potential novel biomarker for UBC diagnosis/prognosis and an appealing new target in its treatment.

RGS Proteins - genetics

Tumor Suppressor Proteins - metabolism

Urothelium - metabolism

Gene Expression - drug effects

Urinary Bladder - metabolism

Butylhydroxybutylnitrosamine - toxicity

Humans

Mice, Inbred C57BL

Tumor Suppressor Protein p53 - metabolism

Cell Transformation, Neoplastic - metabolism

Urinary Bladder Neoplasms - chemically induced

DNA (Cytosine-5-)-Methyltransferase 1 - metabolism

Tumor Suppressor Protein p53 - genetics

Mice, Knockout

Animals

DNA (Cytosine-5-)-Methyltransferase 1 - genetics

Urinary Bladder Neoplasms - genetics

Cell Transformation, Neoplastic - genetics

Tumor Suppressor Proteins - genetics

RGS Proteins - metabolism

Urinary Bladder - drug effects

Cell Transformation, Neoplastic - drug effects

Urothelium - drug effects

Urinary Bladder Neoplasms - metabolism

Details

Title: Subtitle: RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by promoting p53 activation and DNMT1 downregulation
Creators: Jianqi Yang - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Lance T Platt - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Biswanath Maity - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Katelin E Ahlers - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Zili Luo - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Zhibo Lin - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Bandana Chakravarti - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Stella-Rita Ibeawuchi - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Ryan W Askeland - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Jolanta Bondaruk - Department of Pathology, MD Anderson Cancer Center, the University of Texas, Houston, TX, USA
Bogdan A Czerniak - Department of Pathology, MD Anderson Cancer Center, the University of Texas, Houston, TX, USA
Rory A Fisher - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.7(43), pp.69159-69172
DOI: 10.18632/oncotarget.12473
PMID: 27713144
PMCID: PMC5342467
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: United States
Grant note: R01 CA161882 / NCI NIH HHS
Language: English
Date published: 10/25/2016
Academic Unit: Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040291202771

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