癌细胞表现出表型可塑性和表观遗传重编程，这使得它们能够通过采用谱系可塑性来逃避谱系依赖性靶向治疗。癌细胞利用表观遗传调控机制获得谱系可塑性和治疗耐药性的潜在机制仍知之甚少。我们确定锌指蛋白 397 (ZNF397) 是雄激素受体 (AR) 的真正共激活剂，对于控制 AR 驱动的管腔谱系的转录程序至关重要。 ZNF397 缺陷促进癌细胞从 AR 驱动的管腔谱系转变为 10-11 易位 2 (TET2) 驱动的谱系可塑状态，最终促进对抑制 AR 信号传导的治疗产生耐药性。有趣的是，我们的研究结果表明 TET2 抑制剂可以消除 ZNF397 缺陷肿瘤中 AR 靶向治疗的耐药性。这些见解揭示了前列腺癌和乳腺癌通过表观遗传重连获得谱系可塑性的新机制，并为旨在克服谱系可塑性决定的治疗耐药性的临床干预提供了有希望的意义。这项研究揭示了调节肿瘤谱系可塑性和治疗反应的新表观遗传机制，增强对耐药性的了解，并揭示前列腺癌和其他恶性肿瘤的新治疗策略。我们的研究结果还阐明了 TET2 的致癌作用，并从机制上将 TET2 驱动的表观遗传重连与谱系可塑性和治疗耐药性联系起来。

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.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.