ONECUT2 is a driver of neuroendocrine prostate cancer. Academic Article uri icon

Overview

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.

authors

publication date

  • January 17, 2019

Research

keywords

  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Neuroendocrine Tumors
  • Prostatic Neoplasms
  • Smad3 Protein
  • Transcription Factors

Identity

PubMed Central ID

  • PMC6336817

Scopus Document Identifier

  • 85060134209

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-08133-6

PubMed ID

  • 30655535

Additional Document Info

volume

  • 10

issue

  • 1