Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency

Yu Ching Wen, Wei Yu Chen, Van Thi Ngoc Tram, Hsiu Lien Yeh, Wei Hao Chen, Kuo Ching Jiang, Wassim Abou-Kheir, Jiaoti Huang, Michael Hsiao, Yen Nien Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroendocrine differentiation (NED) frequently occurs in androgen-deprivation therapy (ADT)-resistant prostate cancer (PCa) and is typically associated with metabolic pathway alterations, acquisition of lineage plasticity, and malignancy. There is no conventional therapeutic approach for PCa patients with NED pathologic features because the molecular targets are unknown. Here, we evaluated the regulatory mechanism of NED-associated metabolic reprogramming induced by ADT. We detected that the loss of the androgen-responsive transcription factor, zinc finger, and BTB domain containing 10 (ZBTB10), can activate pyruvate kinase L/R (PKLR) to enhance a NED response that is associated with glucose uptake by PCa cells. PKLR exhibits a tumor-promoting effect in PCa after ADT, but ZBTB10 can compensate for the glucose metabolism and NED capacity of PKLR through the direct transcriptional downregulation of PKLR. Targeting PKLR by drug repurposing with FDA-approved compounds can reduce the aggressiveness and NED of ADT-resistant PCa. We demonstrated that PKLR acts as a modulator to activate NED in PCa enhancement by loss of ZBTB10, thereby enabling PCa cells to mount a glycolysis response essential for therapeutic resistance. Our findings highlight the broad relation between NED and metabolic dysfunction to provide gene expression-based biomarkers for NEPC treatment.

Original languageEnglish
Article number252
JournalCell Death and Disease
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2022

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency'. Together they form a unique fingerprint.

Cite this