Malik Rohit, Khan Amjad P, Asangani Irfan A, Cieślik Marcin, Prensner John R, Wang Xiaoju, Iyer Matthew K, Jiang Xia, Borkin Dmitry, Escara-Wilke June, Stender Rachell, Wu Yi-Mi, Niknafs Yashar S, Jing Xiaojun, Qiao Yuanyuan, Palanisamy Nallasivam, Kunju Lakshmi P, Krishnamurthy Pranathi M, Yocum Anastasia K, Mellacheruvu Dattatreya, Nesvizhskii Alexey I, Cao Xuhong, Dhanasekaran Saravana M, Feng Felix Y, Grembecka Jolanta, Cierpicki Tomasz, Chinnaiyan Arul M
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nat Med. 2015 Apr;21(4):344-52. doi: 10.1038/nm.3830. Epub 2015 Mar 30.
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
对雄激素剥夺疗法的抗性以及雄激素受体（AR）活性的增加是去势抵抗性前列腺癌（CRPC）的主要驱动因素。尽管先前的研究主要集中在直接靶向AR，但AR信号的共激活因子可能代表新的治疗靶点，对此研究相对较少。在此，我们证明混合谱系白血病蛋白（MLL）复合物，一种众所周知的MLL融合阳性白血病驱动因子，可作为AR信号的共激活因子。AR通过menin-MLL亚基直接与MLL复合物相互作用。在CRPC中，menin的表达高于激素初治前列腺癌和良性前列腺组织，且menin高表达与前列腺癌确诊患者的总生存期较差相关。用一种小分子抑制剂阻断menin-MLL相互作用可抑制AR信号，并在体内抑制小鼠去势抵抗性肿瘤的生长。综上所述，这项研究确定MLL复合物是AR的关键共激活因子以及晚期前列腺癌的潜在治疗靶点。
