Table S3 from ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer

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posted on 2024-08-02, 07:21 authored by 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 Barnes, Mia 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

Table S3. Significantly Enriched or Depleted Signaling Pathways in GSEA Analysis

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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U.S. Department of Defense (DOD)

Cancer Prevention and Research Institute of Texas (CPRIT)

Prostate Cancer Foundation (PCF)

Welch Foundation (The Welch Foundation)

Terry Fox Foundation (La Fondation Terry Fox)

Life Sciences Research Foundation (LSRF)

History

ARTICLE 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 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.