PROX1 is an early driver of lineage plasticity in prostate cancer
(2025) In Journal of Clinical Investigation 135(11).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2025-06-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 135
- issue
- 11
- article number
- e187490
- publisher
- American Society for Clinical Investigation
- external identifiers
-
- pmid:40454483
- scopus:105007736108
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI187490
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025, Duan et al.
- id
- 0ad0775c-5b92-4fb4-a4c2-ae28567508c1
- date added to LUP
- 2025-12-16 15:31:41
- date last changed
- 2025-12-17 08:42:25
@article{0ad0775c-5b92-4fb4-a4c2-ae28567508c1,
abstract = {{<p>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.</p>}},
author = {{Duan, Zhi and Shi, Mingchen and Kumaraswamy, Anbarasu and Lin, Dong and Khokhani, Dhruv and Wang, Yong and Zhang, Chao and Flores, Diana and Rodansky, Eva and Swaim, Olivia A. and Storck, William K. and Beck, Hannah N. and Patel, Radhika A. and Sayar, Erolcan and Hanratty, Brian P. and Xue, Hui and Dong, Xin and Maylin, Zoe R. and Wan, Rensheng and Quigley, David A. and Sjöström, Martin and Hu, Ya Mei and Zhao, Faming and Xia, Zheng and Cheng, Siyuan and Yu, Xiuping and Feng, Felix Y. and Zhang, Li and Aggarwal, Rahul and Small, Eric J. and Ravikumar, Visweswaran and Rao, Arvind and Bedi, Karan and Lee, John K. and Morrissey, Colm and Coleman, Ilsa and Nelson, Peter S. and Corey, Eva and Udager, Aaron M. and Rebernick, Ryan J. and Cieslik, Marcin P. and Chinnaiyan, Arul M. and Yates, Joel A. and Haffner, Michael C. and Wang, Yuzhuo and Alumkal, Joshi J.}},
issn = {{0021-9738}},
language = {{eng}},
month = {{06}},
number = {{11}},
publisher = {{American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{PROX1 is an early driver of lineage plasticity in prostate cancer}},
url = {{http://dx.doi.org/10.1172/JCI187490}},
doi = {{10.1172/JCI187490}},
volume = {{135}},
year = {{2025}},
}