Transcriptional Regulation by KLF6, A Novel Tumor Suppressor Gene in Prostate Cancer, Through Interaction with HATS and HDACS
Annual rept. 1 Mar 2005-28 Feb 2006
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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KLF6 is a zinc finger transcription factor mutated in more than 50 of sporadic prostate cancers. Our studies have explored the role of acetylation of KLF6 and how its abrogation by mutation in human cancer may contribute to its dysregulation and emergence of prostate cancer. The KLF6 tumor suppressor protein normally inhibits cell growth by upregulating p21 WAF1CIP1 independent of p53 whereas most tumor derived mutations are no longer growth suppressive Narla et al Science 2942563,2001. We have demonstrated by chromatin that transactivation of p21 by KLF6 occurs through its direct recruitment to the p21 promoter and requires acetylation by histone acetyltransferase activity. Based on these data we have extended findings to uncover additional cancers in which KLF6 is dsyregulated and have defined a novel pathway of KLF6 dysregulation through generation of dominant negative alternative splice forms that are overexpressed in many cancers. These data suggest that multiple mechanisms including loss of acetylation contribution to KLF6 dysregulation that contributes to carcinogenesis in prostate and other cancers.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology