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2016 ; 7
(43
): 69159-69172
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RGS6 is an essential tumor suppressor that prevents bladder carcinogenesis by
promoting p53 activation and DNMT1 downregulation
#MMPMID27713144
Yang J
; Platt LT
; Maity B
; Ahlers KE
; Luo Z
; Lin Z
; Chakravarti B
; Ibeawuchi SR
; Askeland RW
; Bondaruk J
; Czerniak BA
; Fisher RA
Oncotarget
2016[Oct]; 7
(43
): 69159-69172
PMID27713144
show ga
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.
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