TY - JOUR
T1 - Siah2-Dependent Concerted Activity of HIF and FoxA2 Regulates Formation of Neuroendocrine Phenotype and Neuroendocrine Prostate Tumors
AU - Qi, Jianfei
AU - Nakayama, Koh
AU - Cardiff, Robert D.
AU - Borowsky, Alexander D.
AU - Kaul, Karen
AU - Williams, Roy
AU - Krajewski, Stan
AU - Mercola, Dan
AU - Carpenter, Philip M.
AU - Bowtell, David
AU - Ronai, Ze'ev A.
N1 - Funding Information:
We thank members of the Ronai Lab for helpful discussions. We thank Drs. Lorenz Poellinger, Hueng-Sik Choi, Wei Gu, Andreas Möller, Collin House, Robert Abraham, Gary Chiang, Norman Greenberg, James Jacobberger, Marja Nevalainen, for reagents, Jeremy Mathews for preparation of the prostate tumor TMA, Ling Wang for help with intraprostatic injection, Joan Massague for protocol of retroviral infections. Support by NCI grant CA111515 (to Z.A.R.), P50CA090386 (K.K.), and U01CA114810 (to D.M.) is gratefully acknowledged. J.Q. was supported by a CIHR fellowship.
PY - 2010/7
Y1 - 2010/7
N2 - Neuroendocrine (NE) phenotype, seen in >30% of prostate adenocarcinomas (PCa), and NE prostate tumors are implicated in aggressive prostate cancer. Formation of NE prostate tumors in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, which regulates HIF-1α availability. Cooperation between HIF-1α and FoxA2, a transcription factor expressed in NE tissue, promotes recruitment of p300 to transactivate select HIF-regulated genes, Hes6, Sox9, and Jmjd1a. These HIF-regulated genes are highly expressed in metastatic PCa and required for hypoxia-mediated NE phenotype, metastasis in PCa, and the formation of NE tumors. Tissue-specific expression of FoxA2 combined with Siah2-dependent HIF-1α availability enables a transcriptional program required for NE prostate tumor development and NE phenotype in PCa.
AB - Neuroendocrine (NE) phenotype, seen in >30% of prostate adenocarcinomas (PCa), and NE prostate tumors are implicated in aggressive prostate cancer. Formation of NE prostate tumors in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, which regulates HIF-1α availability. Cooperation between HIF-1α and FoxA2, a transcription factor expressed in NE tissue, promotes recruitment of p300 to transactivate select HIF-regulated genes, Hes6, Sox9, and Jmjd1a. These HIF-regulated genes are highly expressed in metastatic PCa and required for hypoxia-mediated NE phenotype, metastasis in PCa, and the formation of NE tumors. Tissue-specific expression of FoxA2 combined with Siah2-dependent HIF-1α availability enables a transcriptional program required for NE prostate tumor development and NE phenotype in PCa.
UR - http://www.scopus.com/inward/record.url?scp=77954291438&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2010.05.024
DO - 10.1016/j.ccr.2010.05.024
M3 - Article
C2 - 20609350
AN - SCOPUS:77954291438
SN - 1535-6108
VL - 18
SP - 23
EP - 38
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -