Epigenetic silencing of a Ca2+-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers
- Hongchuan Jin*,
- Xian Wang*,
- Jianming Ying*,
- Ada H. Y. Wong*,
- Yan Cui*,
- Gopesh Srivastava†,
- Zhong-Ying Shen‡,
- En-Min Li‡,
- Qian Zhang§,
- Jie Jin§,
- Sabine Kupzig¶,
- Anthony T. C. Chan*,
- Peter J. Cullen¶,‖, and
- Qian Tao*,‡,‖
- *Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir Y. K. Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong;
- †Department of Pathology, University of Hong Kong, Hong Kong;
- ‡Shantou University Medical College/Chinese University of Hong Kong Joint Epigenetics Group, Shantou University Medical College, Shantou 515041, China;
- §Department of Urology, Peking University First Hospital and Institute of Urology, Beijing 100034, China; and
- ¶The Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom
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Edited by Anthony J. Pawson, University of Toronto, Toronto, ON, Canada, and approved June 18, 2007 (received for review January 8, 2007)
Abstract
Ras has achieved notoriety as an oncogene aberrantly activated in multiple human tumors. Approximately 30% of all human tumors express an oncogenic form of this GTPase that is locked in an active conformation as a result of being insensitive to Ras GTPase-activating proteins (GAPs), proteins that normally regulate the inactivation of Ras by enhancing its intrinsic GTPase activity. Besides oncogenic mutations in Ras, signaling by wild-type Ras is also frequently deregulated in tumors through aberrant coupling to activated cell surface receptors. This indicates that alternative mechanisms of aberrant wild-type Ras activation may be involved in tumorigenesis. Here, we describe another mechanism through which aberrant Ras activation is achieved in human cancers. We have established that Ras GTPase-activating-like protein (RASAL), a Ca2+-regulated Ras GAP that decodes the frequency of Ca2+ oscillations, is silenced through CpG methylation in multiple tumors. With the finding that ectopic expression of catalytically active RASAL leads to growth inhibition of these tumor cells by Ras inactivation, we have provided evidence that epigenetically silencing of this Ras GAP represents a mechanism of aberrant Ras activation in certain cancers. Our demonstration that RASAL constitutes a tumor suppressor gene has therefore further emphasized the importance of Ca2+ in the regulation of Ras signaling and has established that deregulation of this pathway is an important step in Ras-mediated tumorigenesis.
Footnotes
- ‖To whom correspondence may be addressed. E-mail: pete.cullen{at}bris.ac.uk or qtao{at}clo.cuhk.edu.hk
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Author contributions: H.J., P.J.C., and Q.T. designed research; H.J., X.W., J.Y., A.H.Y.W., Y.C., and G.S. performed research; G.S., Z.-Y.S., E.-M.L., Q.Z., J.J., S.K., A.T.C.C., and P.J.C. contributed new reagents/analytic tools; H.J., X.W., J.Y., and Q.T. analyzed data; and H.J., P.J.C., and Q.T. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0700153104/DC1.
- Abbreviations:
- BGS,
- bisulfite genomic sequencing;
- Btk,
- Bruton's tyrosine kinase;
- [Ca2+]i,
- intracellular free Ca2+ concentration;
- CGI,
- CpG island;
- GAP,
- GTPase-activating protein;
- GEF,
- guanine nucleotide exchange factor;
- MSP,
- methylation-specific PCR.
- © 2007 by The National Academy of Sciences of the USA
