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ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer

Xu, Yaru ; Yang, Yuqiu ; Wang, Zhaoning ; Sjöström, Martin LU ; Jiang, Yuyin ; Tang, Yitao ; Cheng, Siyuan ; Deng, Su ; Wang, Choushi and Gonzalez, Julisa , et al. (2024) In Cancer Discovery 14(8). p.1496-1521
Abstract

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR... (More)

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Male, Humans, DNA-Binding Proteins/genetics, Dioxygenases, Receptors, Androgen/metabolism, Prostatic Neoplasms/drug therapy, Drug Resistance, Neoplasm/genetics, Proto-Oncogene Proteins/genetics, Mice, Animals, Cell Line, Tumor, Epigenesis, Genetic, Cell Lineage
in
Cancer Discovery
volume
14
issue
8
pages
1496 - 1521
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85200523904
  • pmid:38591846
ISSN
2159-8274
DOI
10.1158/2159-8290.CD-23-0539
language
English
LU publication?
no
additional info
©2024 The Authors; Published by the American Association for Cancer Research.
id
5d2eb4d9-2eeb-4b71-90dd-2369d1b8bc1f
date added to LUP
2026-02-10 16:49:48
date last changed
2026-02-11 04:01:27
@article{5d2eb4d9-2eeb-4b71-90dd-2369d1b8bc1f,
  abstract     = {{<p>Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance.</p>}},
  author       = {{Xu, Yaru and Yang, Yuqiu and Wang, Zhaoning and Sjöström, Martin and Jiang, Yuyin and Tang, Yitao and Cheng, Siyuan and Deng, Su and Wang, Choushi and Gonzalez, Julisa and Johnson, Nickolas A and Li, Xiang and Li, Xiaoling and Metang, Lauren A and Mukherji, Atreyi and Xu, Quanhui and Tirado, Carla R and Wainwright, Garrett and Yu, Xinzhe and Barnes, Spencer and Hofstad, Mia and Chen, Yu and Zhu, Hong and Hanker, Ariella B and Raj, Ganesh V and Zhu, Guanghui and He, Housheng H and Wang, Zhao and Arteaga, Carlos L and Liang, Han and Feng, Felix Y and Wang, Yunguan and Wang, Tao and Mu, Ping}},
  issn         = {{2159-8274}},
  keywords     = {{Male; Humans; DNA-Binding Proteins/genetics; Dioxygenases; Receptors, Androgen/metabolism; Prostatic Neoplasms/drug therapy; Drug Resistance, Neoplasm/genetics; Proto-Oncogene Proteins/genetics; Mice; Animals; Cell Line, Tumor; Epigenesis, Genetic; Cell Lineage}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{1496--1521}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Discovery}},
  title        = {{ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer}},
  url          = {{http://dx.doi.org/10.1158/2159-8290.CD-23-0539}},
  doi          = {{10.1158/2159-8290.CD-23-0539}},
  volume       = {{14}},
  year         = {{2024}},
}