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
Affiliations
Wei-Yu Chen
Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Phan Vu Thuy Dung
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Hsiu-Lien Yeh
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Wei-Hao Chen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Kuo-Ching Jiang
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Han-Ru Li
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Zi-Qing Chen
Division of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
Michael Hsiao
Genomics Research Center, Academia Sinica, Taipei, Taiwan
Jiaoti Huang
Department of Pathology, Duke University Medical Center, Durham, NC, USA
Yu-Ching Wen
Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Corresponding author. Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
Yen-Nien Liu
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Corresponding author. Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
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.
