Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA.
Nat Commun. 2018 Feb 5;9(1):500. doi: 10.1038/s41467-018-02863-3.
BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth.
BMI1 是多梳抑制复合物 1（PRC1）的一个关键组成部分，通过增强 RING1B 的酶活性，使组蛋白 H2A 在赖氨酸 119 上泛素化，从而抑制基因转录，发挥其致癌功能。在这里，我们报道了 BMI1 的一个 PRC1 非依赖性作用，这对于去势抵抗性前列腺癌（CRPC）的进展至关重要。BMI1 与雄激素受体（AR）结合，并阻止 MDM2 介导的 AR 蛋白降解，从而导致前列腺癌细胞中持续的 AR 信号转导。更重要的是，我们证明，靶向 BMI1 可以有效地抑制对手术去势和恩杂鲁胺治疗产生耐药性的异种移植瘤的肿瘤生长。这些结果表明，单独阻断 BMI1 或与抗 AR 治疗联合使用可能更有效地抑制前列腺肿瘤生长。
