ABSTRACT Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen deprivation therapy (ADT), and it ultimately develops into an aggressive

subset of this disease. However, the contribution of signaling pathways that lead to metabolic disorders and NE differentiation of prostate cancer remains unclear. In this study, we

identified that ADT induced upregulation of the succinate-CoA ligase GDP-forming beta subunit (SUCLG2), which regulates succinate metabolism and NE differentiation of prostate cancer. We

demonstrated a connection that upregulation of epidermal growth factor receptor (EGFR)-leukemia inhibitory factor receptor (LIFR) signaling induced SUCLG2 expression in prostate cancer

cells. Knockdown of SUCLG2 suppressed NE differentiation in cultured cells and reduced prostate tumor growth in a xenograft model. Analysis of prostate tissue samples showed increased

intensity of nuclear EGFR associated with the LIFR and SUCLG2 in castration-resistant prostate cancer tumors. Our study provides a mechanism whereby ADT upregulates EGFR–LIFR signaling that

activates SUCLG2, which subsequently stimulates the metabolic changes associated with NE differentiation and aggressive prostate cancer phenotype. Access through your institution Buy or

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PYRUVATE KINASE L/R LINKS METABOLISM DYSFUNCTION TO NEUROENDOCRINE DIFFERENTIATION OF PROSTATE CANCER BY ZBTB10 DEFICIENCY Article Open access 19 March 2022 KIF1A PROMOTES NEUROENDOCRINE

DIFFERENTIATION IN PROSTATE CANCER BY REGULATING THE OGT-MEDIATED O-GLCNACYLATION Article Open access 06 November 2024 NERVE GROWTH FACTOR INTERACTS WITH CHRM4 AND PROMOTES NEUROENDOCRINE

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references ACKNOWLEDGEMENTS This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST108-2320-B-038-047) to WYC, (MOST 109-2314-B-038-105) to YCW,

and (MOST109-2326-B-038-001-MY3) to YNL, Taipei Medical University—Wan Fang Hospital (109TMU-WFH-01) to WYC, and the National Health Research Institute of Taiwan (NHRI-EX109-10702BI) to

YNL. AUTHOR INFORMATION Author notes * These authors contributed equally: Shian-Ren Lin, Yu-Ching Wen AUTHORS AND AFFILIATIONS * Graduate Institute of Cancer Biology and Drug Discovery,

College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan Shian-Ren Lin, Kuo-Ching Jiang, Wei-Hao Chen, Ntlotlang Mokgautsi & Yen-Nien Liu * Department of

Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Yu-Ching Wen * Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Yu-Ching Wen * Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan Hsiu-Lien Yeh * Department of Pathology, Duke University Medical Center,

Durham, NC, USA Jiaoti Huang & Yen-Nien Liu * Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Wei-Yu Chen * Department of Pathology, School of

Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan Wei-Yu Chen Authors * Shian-Ren Lin View author publications You can also search for this author inPubMed Google

Scholar * Yu-Ching Wen View author publications You can also search for this author inPubMed Google Scholar * Hsiu-Lien Yeh View author publications You can also search for this author

inPubMed Google Scholar * Kuo-Ching Jiang View author publications You can also search for this author inPubMed Google Scholar * Wei-Hao Chen View author publications You can also search for

this author inPubMed Google Scholar * Ntlotlang Mokgautsi View author publications You can also search for this author inPubMed Google Scholar * Jiaoti Huang View author publications You

can also search for this author inPubMed Google Scholar * Wei-Yu Chen View author publications You can also search for this author inPubMed Google Scholar * Yen-Nien Liu View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS WYC and YNL designed the experiments and supervised the project. SRL, HLY, KCJ, and WHC performed the

experiments. YCW, WYC, and JH provided the human prostate cancer samples. WYC performed the histomorphometric analysis. HLY constructed the databases and performed the statistical and

computational analyses. SRL, YCW, WYC, and YNL wrote, reviewed, and/or revised the manuscript. All authors analyzed and interpreted the data. CORRESPONDING AUTHORS Correspondence to Wei-Yu

Chen or Yen-Nien Liu. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ETHICAL APPROVAL Tissue samples were used in accordance with the

Declaration of Helsinki and U.S. Common Rule, and their use was approved by the Taipei Medical University—Joint Institutional Review Board (approval no. N201711067) and the Duke University

School of Medicine—Institutional Review Board (protocol ID, Pro00070193). ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lin,

SR., Wen, YC., Yeh, HL. _et al._ EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. _Oncogene_ 39, 6757–6775 (2020).

https://doi.org/10.1038/s41388-020-01468-9 Download citation * Received: 08 May 2020 * Revised: 23 August 2020 * Accepted: 10 September 2020 * Published: 22 September 2020 * Issue Date: 29

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