PROX1 is an early driver of lineage plasticity in prostate cancer
Zhi Duan, … , Yuzhuo Wang, Joshi J. Alumkal
Zhi Duan, … , Yuzhuo Wang, Joshi J. Alumkal
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e187490. https://doi.org/10.1172/JCI187490.
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Research Article Cell biology Oncology

PROX1 is an early driver of lineage plasticity in prostate cancer

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.

Authors

Zhi Duan, Mingchen Shi, Anbarasu Kumaraswamy, Dong Lin, Dhruv Khokhani, Yong Wang, Chao Zhang, Diana Flores, Eva Rodansky, Olivia A. Swaim, William K. Storck, Hannah N. Beck, Radhika A. Patel, Erolcan Sayar, Brian P. Hanratty, Hui Xue, Xin Dong, Zoe R. Maylin, Rensheng Wan, David A. Quigley, Martin Sjöström, Ya-Mei Hu, Faming Zhao, Zheng Xia, Siyuan Cheng, Xiuping Yu, Felix Y. Feng, Li Zhang, Rahul Aggarwal, Eric J. Small, Visweswaran Ravikumar, Arvind Rao, Karan Bedi, John K. Lee, Colm Morrissey, Ilsa Coleman, Peter S. Nelson, Eva Corey, Aaron M. Udager, Ryan J. Rebernick, Marcin P. Cieslik, Arul M. Chinnaiyan, Joel A. Yates, Michael C. Haffner, Yuzhuo Wang, Joshi J. Alumkal

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Figure 1

PROX1 is upregulated in patient samples exhibiting AR pathway loss and lineage plasticity.

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PROX1 is upregulated in patient samples exhibiting AR pathway loss and l...
(A) Differentially upregulated genes ranked by adjusted P (Padj) value in prostate cancer patient tumors that converted to DNPC after enzalutamide treatment are shown from the Westbrook et al. 2022 cohort (6). PROX1 is the top-ranked gene. (B–D) PROX1 mRNA levels were quantified by RNA-Seq in the indicated molecular subtypes of prostate cancer patient tumors from 3 different cohorts: Labrecque et al. 2019 (n = 98) (9) (B), WCDT (n = 210) (8, 22) (C), and Beltran et al. 2016 (n = 49) (7) (D). Molecular subtypes ARPC (AR+NE–), amphicrine (AR+NE+), AR activity–low (ARlowNE–), DNPC (AR–NE–), and NEPC (AR–NE+) are indicated with the sample sizes of each group. Data are reported as the mean ± SD. P values were calculated by unpaired 2-sample Wilcoxon’s test with Benjamini-Hochberg correction for multiple comparison (B and C) and unpaired 2-sample Wilcoxon’s test (D). *P < 0.05; ***P < 0.001; ****P < 0.0001. (E and F) Kaplan-Meier curves represent overall survival probability for patients in the WCDT (8, 22) (E) or Abida et al. 2019 (23) (F) cohort stratified by quantiles of PROX1 expression. Q1 represents the lowest-quartile group, and Q4 represents the highest-quartile group. The log-rank test was used to determine significance.