例如:"lncRNA", "apoptosis", "WRKY"

KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC.

Oncogene. 2019 Jan;38(1):17-32. Epub 2018 Aug 02
Hung-Jung Wang 1 , Mamata Pochampalli 2 , Ling-Yu Wang 2 , June X Zou 2 , Pei-Shan Li 3 , Sheng-Chieh Hsu 4 , Bi-Juan Wang 5 , Shih-Han Huang 5 , Ping Yang 6 , Joy C Yang 7 , Cheng-Ying Chu 8 , Chia-Ling Hsieh 8 , Shian-Ying Sung 8 , Chien-Feng Li 9 , Clifford G Tepper 7 , David K Ann 10 , Allen C Gao 7 , Christopher P Evans 11 , Yoshihiro Izumiya 11 , Chi-Pin Chuu 5 , Wen-Ching Wang 12 , Hong-Wu Chen 11 , Hsing-Jien Kung 13
Hung-Jung Wang 1 , Mamata Pochampalli 2 , Ling-Yu Wang 2 , June X Zou 2 , Pei-Shan Li 3 , Sheng-Chieh Hsu 4 , Bi-Juan Wang 5 , Shih-Han Huang 5 , Ping Yang 6 , Joy C Yang 7 , Cheng-Ying Chu 8 , Chia-Ling Hsieh 8 , Shian-Ying Sung 8 , Chien-Feng Li 9 , Clifford G Tepper 7 , David K Ann 10 , Allen C Gao 7 , Christopher P Evans 11 , Yoshihiro Izumiya 11 , Chi-Pin Chuu 5 , Wen-Ching Wang 12 , Hong-Wu Chen 11 , Hsing-Jien Kung 13
+ et al

[No authors listed]

Author information
  • 1 Institute of Molecular and Genomic Medicine, National Health Research Institutes, 35053, Miaoli County, Taiwan. hjwang@nhri.org.tw.
  • 2 Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, 95817, USA.
  • 3 Institute of Molecular and Genomic Medicine, National Health Research Institutes, 35053, Miaoli County, Taiwan.
  • 4 Institute of Biotechnology, National Tsing-Hua University, 30035, Hsinchu, Taiwan.
  • 5 Institute of Cellular and System Medicine, National Health Research Institutes, 35053, Miaoli County, Taiwan.
  • 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 7 Department of Urology, School of Medicine, University of California, Davis, CA, 95817, USA.
  • 8 Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan.
  • 9 National Institute of Cancer Research, National Health Research Institutes, 35053, Miaoli County, Taiwan.
  • 10 Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 11 Comprehensive Cancer Center, School of Medicine, University of California, Davis, Sacramento, CA, USA.
  • 12 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan.
  • 13 Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan. hkung@nhri.org.tw.

摘要


During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance. Previously, we showed that KDM8 is involved in the regulation of cell cycle and tumor metabolism in breast cancer cells. Its role in prostate cancer has not been explored. Here, we show that KDM8's oncogenic properties in prostate cancer come from its direct interaction (1) with AR to affect androgen response and (2) with PKM2 to regulate tumor metabolism. The interaction with AR leads to the elevated expression of androgen response genes in androgen-deprived conditions. They include ANCCA/ATAD2 and EZH2, which are directly targeted by KDM8 and involved in sustaining the survival of the cells under hormone-deprived conditions. Notably, in enzalutamide-resistant cells, the expressions of both KDM8 and EZH2 are further elevated, so are neuroendocrine markers. Consequently, EZH2 inhibitors or KDM8 knockdown both resensitize the cells toward enzalutamide. In the cytosol, KDM8 associates with PKM2, the gatekeeper of pyruvate flux and translocates PKM2 into the nucleus, where the KDM8/PKM2 complex serves as a coactivator of HIF-1α to upregulate glycolytic genes. Using shRNA knockdown, we validate KDM8's functions as a regulator for both androgen-responsive and metabolic genes. KDM8 thus presents itself as an ideal therapeutic target for metabolic adaptation and castration-resistance of prostate cancer cells.