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

Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjöström, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A. Johnson, Xiang Li, Xiaoling Li, Lauren A. Metang, Atreyi Mukherji, Quanhui Xu, Carla R. Tirado, Garrett Wainwright, Xinzhe Yu, Spencer BarnesMia Hofstad, Yu Chen, Hong Zhu, Ariella B. Hanker, Ganesh V. Raj, Guanghui Zhu, Housheng H. He, Zhao Wang, Carlos L. Arteaga, Han Liang, Felix Y. Feng, Yunguan Wang, Tao Wang, Ping Mu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 machin-ery 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.

Original languageEnglish (US)
Pages (from-to)1496-1521
Number of pages26
JournalCancer discovery
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2024

ASJC Scopus subject areas

  • Oncology

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