The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis
Annual rept. 30 Sep 2011-29 Sep 2012
JEFFERSON MEDICAL COLL PHILADELPHIA PA
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The recurrence of prostate cancer is mainly due to the transition of initially androgen-dependent cellular proliferation to androgen-independent growth, or castration-resistant prostate cancers CRPC. To improve the current therapeutic efficiencies, understanding the mechanisms is critical for developing novel strategies. We found that cell fate determine factor DACH1 regulated AR signaling and androgen-dependent growth. We hypothesis that DACH1Six1Eya pathway is an endogenous regulator of AR trans-activation and contributes to prostate tumor onset and progression. New studies demonstrated that DACH1 inhibited the prostate cancer cellular proliferation, not only on AR positive and androgenindependent C4-2 cells but also on AR negative PC-3 and 22RV1 cells. DACH1 inhibited in vitro cellular migration, invasion and tumor growth of PC-3 cells. mRNA microarray analyses and functional validation indicate that repression of IL-6 signaling by DACH1 may be a key molecular mechanism. Inhibitory function of Eya1 on AR transactivation required a phosphates activity and could be enhanced by ectopic expression of co-repressors. Together, our studies show that conserved DACHSixEya pathway regulates hormone signaling and prostate cellular growth. The results may provide a new mechanism for controlling AR signaling transduction and prostate tumorigenesis.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research