2. Academic Validation
  3. PROX1 is an early driver of lineage plasticity in prostate cancer

PROX1 is an early driver of lineage plasticity in prostate cancer

  • J Clin Invest. 2025 Jun 2;135(11):e187490. doi: 10.1172/JCI187490.
Zhi Duan 1 2,  Mingchen Shi 3 4 5,  Anbarasu Kumaraswamy 1 2,  Dong Lin 3 4 5,  Dhruv Khokhani 1 2,  Yong Wang 3 4 5,  Chao Zhang 1 2,  Diana Flores 1 2,  Eva Rodansky 1 2,  Olivia A Swaim 1 2,  William K Storck 1 2,  Hannah N Beck 1 2,  Radhika A Patel 6,  Erolcan Sayar 6,  Brian P Hanratty 6,  Hui Xue 3 4 5,  Xin Dong 3 4 5,  Zoe R Maylin 3 4 5,  Rensheng Wan 7 8,  David A Quigley 7 9 10,  Martin Sjöström 7 8 11 12,  Ya-Mei Hu 13 14,  Faming Zhao 13 14,  Zheng Xia 13 14,  Siyuan Cheng 15,  Xiuping Yu 15,  Felix Y Feng 7 8 10,  Li Zhang 7 9,  Rahul Aggarwal 7 16,  Eric J Small 7 16,  Visweswaran Ravikumar 17,  Arvind Rao 2 17 18 19,  Karan Bedi 2 20,  John K Lee 21,  Colm Morrissey 22,  Ilsa Coleman 6,  Peter S Nelson 6 23,  Eva Corey 22,  Aaron M Udager 2 24 25,  Ryan J Rebernick 17 24 25,  Marcin P Cieslik 17 24 25,  Arul M Chinnaiyan 2 24 25 26,  Joel A Yates 1 2,  Michael C Haffner 6 23 27,  Yuzhuo Wang 3 4 5,  Joshi J Alumkal 1 2 25
Affiliations

Affiliations

  • 1 Department of Internal Medicine and.
  • 2 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
  • 3 Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
  • 4 Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 5 BC Cancer Research Institute, BC Cancer, Vancouver, British Columbia, Canada.
  • 6 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 7 Helen Diller Family Comprehensive Cancer Center.
  • 8 Department of Radiation Oncology.
  • 9 Department of Epidemiology & Biostatistics, and.
  • 10 Department of Urology, UCSF, San Francisco, California, USA.
  • 11 Division of Oncology, Department of Clinical Sciences, Lund, Faculty of Medicine, Lund University, Lund, Sweden.
  • 12 Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
  • 13 Knight Cancer Institute and.
  • 14 Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
  • 15 Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, Louisiana, USA.
  • 16 Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, California, USA.
  • 17 Department of Computational Medicine & Bioinformatics.
  • 18 Department of Biomedical Engineering.
  • 19 Department of Radiation Oncology, and.
  • 20 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
  • 21 Department of Medicine and the Institute for Urologic Oncology, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
  • 22 Department of Urology, University of Washington, Seattle, Washington, USA.
  • 23 Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 24 Department of Pathology.
  • 25 Michigan Center for Translational Pathology, and.
  • 26 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.
  • 27 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
PMID: 40454483 DOI: 10.1172/JCI187490
Abstract

Lineage plasticity is recognized as a critical determinant of lethality and resistance to AR pathway inhibitors in prostate Cancer. Lineage plasticity is a continuum, ranging from AR activity-low tumors, AR-null tumors that do not express a neuroendocrine prostate Cancer (NEPC) program (i.e., double-negative prostate Cancer [DNPC]), and AR-null NEPC tumors. Factors upregulated early in lineage plasticity are not well-characterized. The clarification of such factors is essential to identify tumors undergoing lineage plasticity or at risk of this occurring. Our integrative analysis of metastatic prostate Cancer patient tumors, patient-derived xenografts, and cell models determined that PROX1 is upregulated early in the lineage plasticity continuum and progressively increases as tumors lose AR activity. We determined DNA methylation is a key regulator of PROX1 expression. PROX1 suppression in DNPC and NEPC reduces cell survival and impacts Apoptosis and differentiation, demonstrating PROX1's functional importance. PROX1 is not directly targetable with standard drug development approaches. However, affinity immunopurification demonstrated histone deacetylases (HDACs) are among the top PROX1-interacting proteins; HDAC inhibition depletes PROX1 and recapitulates PROX1 suppression in DNPC and NEPC. Altogether, our results suggest PROX1 promotes the emergence of lineage plasticity, and HDAC inhibition is a promising approach to treat tumors across the lineage plasticity continuum.

Keywords

Cell biology; Epigenetics; Oncology; Prostate cancer.

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