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 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.
Cancer discovery. 2024 Apr 08 [Epub ahead of print]
Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjostrom, 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 Rodriguez Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng Hansen He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu
The University of Texas Southwestern Medical Center, Dallas, TX, United States., University of California, San Diego, La Jolla, California, United States., University of California, San Francisco, San Francisco, CA, United States., The University of Texas MD Anderson Cancer Center, Houston, United States., Louisiana State University Health Sciences Center Shreveport, United States., Baylor College of Medicine, United States., The University of Texas Southwestern Medical Center, Dallas, Texas, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., University of Virginia, Charlottesville, United States., Princess Margaret Cancer Centre, Toronto, Ontario,, Canada., Baylor College of Medicine, Houston, TX, United States., The University of Texas MD Anderson Cancer Center, Houston, TX, United States.