ONECUT2 is a driver of neuroendocrine prostate cancer.
Haiyang GuoXinpei CiMusaddeque AhmedJunjie Tony HuaFraser SoaresDong LinLoredana PucaAram VosoughiHui XueEstelle LiPeiran SuSujun ChenTran NguyenYi LiangYuzhe ZhangXin XuJing XuAnjali V SheahanWail Ba-AlawiSi ZhangOsman MahamudRavi N VellankiMartin GleaveRobert G BristowBenjamin Haibe-KainsJohn T PoirierCharles M RudinMing Sound TsaoBradly G WoutersLadan FazliFelix Y FengLeigh EllisTheo van der KwastAlejandro BerlinMarianne KoritzinskyPaul C BoutrosAmina ZoubeidiHimisha BeltranYuzhuo Z WangHousheng Hansen HePublished in: Nature communications (2019)
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.
Keyphrases
- prostate cancer
- endothelial cells
- transcription factor
- end stage renal disease
- newly diagnosed
- oxidative stress
- chronic kidney disease
- poor prognosis
- ejection fraction
- dna damage
- neuroendocrine tumors
- binding protein
- patient reported
- heat shock protein
- combination therapy
- transforming growth factor
- patient reported outcomes
- dna binding
- heat shock