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ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Xu, Yaru ; Wang, Zhaoning ; Sjöström, Martin LU ; Deng, Su ; Wang, Choushi ; Johnson, Nickolas A ; Gonzalez, Julisa ; Li, Xiaoling ; Metang, Lauren A and Tirado, Carla Rodriguez , et al. (2023)
Abstract

UNLABELLED: Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which 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 co-activator 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... (More)

UNLABELLED: Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which 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 co-activator 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 TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

STATEMENT OF SIGNIFICANCE: This study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2's oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

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publishing date
type
Working paper/Preprint
publication status
published
publisher
bioRxiv
external identifiers
  • pmid:37961351
DOI
10.1101/2023.10.24.563645
language
English
LU publication?
no
id
4a8a2c0a-5d03-41ad-acc8-7019dfe1e045
date added to LUP
2026-02-18 09:14:26
date last changed
2026-02-18 09:14:26
@misc{4a8a2c0a-5d03-41ad-acc8-7019dfe1e045,
  abstract     = {{<p>UNLABELLED: Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which 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 co-activator 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 TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.</p><p>STATEMENT OF SIGNIFICANCE: This study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2's oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.</p>}},
  author       = {{Xu, Yaru and Wang, Zhaoning and Sjöström, Martin and Deng, Su and Wang, Choushi and Johnson, Nickolas A and Gonzalez, Julisa and Li, Xiaoling and Metang, Lauren A and Tirado, Carla Rodriguez and Mukherji, Atreyi and Wainwright, Garrett and Yu, Xinzhe and Yang, Yuqiu and Barnes, Spencer and Hofstad, Mia and Zhu, Hong and Hanker, Ariella and He, Housheng Hansen and Chen, Yu and Wang, Zhao and Raj, Ganesh and Arteaga, Carlos and Feng, Felix and Wang, Yunguan and Wang, Tao and Mu, Ping}},
  language     = {{eng}},
  month        = {{10}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers}},
  url          = {{http://dx.doi.org/10.1101/2023.10.24.563645}},
  doi          = {{10.1101/2023.10.24.563645}},
  year         = {{2023}},
}