Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.
Science signaling. 2024 Jun 11 [Epub]
Yen-Nien Liu, Wei-Yu Chen, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Phan Vu Thuy Dung, Zi-Qing Chen, Wei-Jiunn Lee, Michael Hsiao, Jiaoti Huang, Yu-Ching Wen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan., Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan., Division of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan., Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan., Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan., Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.