BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1.
BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1.
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DOI：
10.1038/s41467-018-02863-3
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发表时间：
2018-02-05
影响因子：
16.6
通讯作者：
Cao Q
中科院分区：
文献类型：
--
作者：
Zhu S;Zhao D;Yan L;Jiang W;Kim JS;Gu B;Liu Q;Wang R;Xia B;Zhao JC;Song G;Mi W;Wang RF;Shi X;Lam HM;Dong X;Yu J;Chen K;Cao Q
BMI1是一种多梳状蛋白，在细胞分化和增殖的表观遗传调控以及肿瘤干细胞的自我更新中发挥重要作用。BMI1在多种癌症中表达上调，包括前列腺癌。作为多梳抑制复合体1(Prc1)的关键成分，BMI1通过增强Ring1b的酶活性，泛素化赖氨酸119位的组蛋白H2A，抑制基因转录，从而发挥其致癌作用。在这里，我们报告了BMI1在去势耐受前列腺癌(CRPC)进展中的关键作用，它不依赖于PRC1。BMI1结合雄激素受体(AR)，阻止MDM2介导的AR蛋白降解，导致前列腺癌细胞中持续的AR信号。更重要的是，我们证明了靶向BMI1有效地抑制了对手术去势和苯扎鲁胺治疗产生抵抗力的异种移植瘤的生长。这些结果表明，单独阻断BMI1或联合抗AR治疗可以更有效地抑制前列腺癌的生长。多梳蛋白BMI1在前列腺癌中高度表达。在这里，作者证明了BMI1直接与AR相互作用，导致AR信号增加，而不依赖于PRC1复合体，并且靶向BMI1抑制了抗去势前列腺癌肿瘤的生长。
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. The polycomb group protein BMI1 is highly expressed in prostate cancer. Here, the authors demonstrate that BMI1 directly interacts with AR leading to increased AR signaling independently of PRC1 complex and that targeting BMI1 inhibits tumor growth of castration-resistant prostate cancer tumors.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1093/bioinformatics/btr490
发表时间：
2011-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Howe EA;Sinha R;Schlauch D;Quackenbush J
通讯作者：
Quackenbush J
影响因子：
16.6
作者：
Gray, Felicia;Cho, Hyo Je;Shukla, Shirish;He, Shihan;Harris, Ashley;Boytsov, Bohdan;Jaremko, Lukasz;Jaremko, Mariusz;Demeler, Borries;Lawlor, Elizabeth R.;Grembecka, Jolanta;Cierpicki, Tomasz
通讯作者：
Cierpicki, Tomasz
影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
11.4
作者：
Lin, HK;Wang, L;Chang, CS
通讯作者：
Chang, CS