MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT

• Published in: Science signaling 2024-06, Vol.17 (840), p.eadc9142
• Main Authors: Liu, Yen-Nien, Chen, Wei-Yu, Yeh, Hsiu-Lien, Chen, Wei-Hao, Jiang, Kuo-Ching, Li, Han-Ru, Dung, Phan Vu Thuy, Chen, Zi-Qing, Lee, Wei-Jiunn, Hsiao, Michael, Huang, Jiaoti, Wen, Yu-Ching
• Format: Article
• Language: English
• Subjects: Androgens - metabolism; Androgens - pharmacology; Animals; Calcium ions; Calcium Signaling - drug effects; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Differentiation; Epithelial-Mesenchymal Transition - drug effects; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-beta - genetics; Hepatocyte Nuclear Factor 3-beta - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Malignancy; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Neuroendocrine Cells - metabolism; Neuroendocrine Cells - pathology; PC-3 Cells; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Symporters; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors
• ISSN: 1945-0877; 1937-9145; 1937-9145
• DOI: 10.1126/scisignal.adc9142

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 Ca sensing function and multiple Ca -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 Ca 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 Ca and suggest its potential as a therapeutic target.