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

Publication ,  Journal Article
Wen, Y-C; Chen, W-Y; Tram, VTN; Yeh, H-L; Chen, W-H; Jiang, K-C; Abou-Kheir, W; Huang, J; Hsiao, M; Liu, Y-N
Published in: Cell Death Dis
March 19, 2022

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.

Duke Scholars

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Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

March 19, 2022

Volume

13

Issue

3

Start / End Page

252

Location

England

Related Subject Headings

  • Repressor Proteins
  • Pyruvate Kinase
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • Male
  • Humans
  • Down-Regulation
  • Androgens
  • Androgen Antagonists
  • 3211 Oncology and carcinogenesis
 

Citation

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Wen, Y.-C., Chen, W.-Y., Tram, V. T. N., Yeh, H.-L., Chen, W.-H., Jiang, K.-C., … Liu, Y.-N. (2022). Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency. Cell Death Dis, 13(3), 252. https://doi.org/10.1038/s41419-022-04694-z
Wen, Yu-Ching, Wei-Yu Chen, Van Thi Ngoc Tram, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Wassim Abou-Kheir, Jiaoti Huang, Michael Hsiao, and Yen-Nien Liu. “Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency.Cell Death Dis 13, no. 3 (March 19, 2022): 252. https://doi.org/10.1038/s41419-022-04694-z.
Wen Y-C, Chen W-Y, Tram VTN, Yeh H-L, Chen W-H, Jiang K-C, et al. Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency. Cell Death Dis. 2022 Mar 19;13(3):252.
Wen, Yu-Ching, et al. “Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency.Cell Death Dis, vol. 13, no. 3, Mar. 2022, p. 252. Pubmed, doi:10.1038/s41419-022-04694-z.
Wen Y-C, Chen W-Y, Tram VTN, Yeh H-L, Chen W-H, Jiang K-C, Abou-Kheir W, Huang J, Hsiao M, Liu Y-N. Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency. Cell Death Dis. 2022 Mar 19;13(3):252.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

March 19, 2022

Volume

13

Issue

3

Start / End Page

252

Location

England

Related Subject Headings

  • Repressor Proteins
  • Pyruvate Kinase
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • Male
  • Humans
  • Down-Regulation
  • Androgens
  • Androgen Antagonists
  • 3211 Oncology and carcinogenesis