Mechanism of DLC1-mediated tumor suppression

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DESCRIPTION (provided by applicant): Deleted in liver cancer 1 (DLC1) is a focal adhesion protein that contains multiple domains including SAM (sterile alpha motif), RhoGAP (RhoGTPase activation protein), and START (steroidogenic acute regulatory (StAR)-related lipid transfer). It was originally isolated as a potential tumor suppressor gene often deleted in hepatocellular carcinoma. Further studies have indicated that down-expression of DLC1 either by genomic deletion or DNA methylation is associated with a variety of cancer types including prostate, lung, breast, kidney, colon, uterus, ovary, and stomach. Mutations in DLC1 that attenuate its expression and function have been identified in prostate and colon cancer. Numerous in vitro data have linked many of DLC1's biological function to its negative regulation of the RhoA pathway through DLC1's RhoGAP domain. On the other hand, the focal adhesion localization is also essential for DLC1's function in suppression of tumor cell growth. Although the critical role of RhoGAP domain on DLC1's function is established, the roles of other domains and novel function of DLC1 are not well studied. In addition, the mechanisms underlying DLC1-mediated tumor suppression in cell culture systems and in an animal remain to be established. We hypothesize that DLC1 is a tumor suppressor that regulates cellular events including cell adhesion, migration, and angiogenesis through its multiple domains; and that loss of its expression or function increases the risk for prostate cancer. The overall goal of this proposal is to systematically determine the domain function of DLC1 and elucidate the molecular mechanisms; to investigate novel functions of DLC1, such as its role in angiogenesis; and to demonstrate its role as a tumor suppressor in the prostate of a mouse and develop better mouse models for prostate cancer, which is the second leading cause of death among men in the United States. There are specific aims to test our hypothesis: Specific Aim 1. Investigation of the molecular mechanism how DLC1 regulates cell shape, adhesion, migration, and tumorigenicity Specific Aim 2. Discovery of new function(s) of DLC1 in preventing prostate cancer development Specific Aim 3. Demonstration of the role of DLC1 in mouse prostate tumorigenesis and establishment of prostate cancer mouse models The results of the proposed studies will contribute significantly to knowledge of the function of DLC1 and molecular mechanisms involved, and provide new ideas and therapeutic approaches for prostate cancer and other cancers that are associated with the loss of DLC1. PUBLIC HEALTH RELEVANCE: Relevance This research is directed toward understanding the mechanism of DLC1-mediated tumor suppression in prostate cancer. Providing evidence for DLC1 contributions to prevention of prostate tumor progression is a prelude to developing methods for therapeutic targeting of its associated pathways. The knowledge may apply to other cancers, since loss of DLC1 is associated with a variety of cancer types.