Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer

Wei Yu Chen, Phan Vu Thuy Dung, Hsiu Lien Yeh, Wei Hao Chen, Kuo Ching Jiang, Han Ru Li, Zi Qing Chen, Michael Hsiao, Jiaoti Huang, Yu Ching Wen, Yen Nien Liu

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

Original languageEnglish
Article number102686
JournalRedox Biology
Volume62
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Androgen deprivation therapy (ADT)
  • MYCN proto-oncogene (MYCN)
  • Neuroendocrine prostate cancer (NEPC)
  • Pyruvate kinase L/R (PKLR)
  • Reactive oxygen species modulator 1 (ROMO1)

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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