Abstract
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.
Highlights
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
We identified 434 genes that are commonly upregulated in NEPC relative to adeno-CRPC (Supplementary Figure 1a)
We identified 927 and 906 genes that are upregulated in the comparisons of poorly differentiated neuroendocrine tumors (NETs) vs. non-NETs in lung and nervous system cancer, respectively (Supplementary Figure 1a)
Summary
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. Treatment with hypoxiaactivated prodrug TH-302 potently reduces NEPC tumor growth These results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients. Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of prostate cancer (PCa) It rarely arises de novo, NEPC may emerge from prostate adenocarcinoma (adeno-PCa) due to lineage plasticity induced by androgen receptor (AR)-targeted therapy[1,2]. Since a single transcription factor (TF) can modulate multiple downstream pathogenesis-related genes, identification of master TFs of NETs could pinpoint more efficacious therapeutic targets for NETs. Since a single transcription factor (TF) can modulate multiple downstream pathogenesis-related genes, identification of master TFs of NETs could pinpoint more efficacious therapeutic targets for NETs To fill this knowledge gap, we performed a pan-cancer analysis of poorly differentiated NET and non-NETs, and identified transcription factor ONECUT2 as a potential master regulator of poorly differentiated NETs. ONECUT2 is significantly upregulated in NEPC compared to adeno-PCa. Ectopic expression of ONECUT2 drives NE plasticity and induces hypoxia response genes in PCa cells. NEPC tend to be more hypoxic than adeno-PCa, suggesting that hypoxia-directed therapy may benefit patients with NEPC
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