Targeting the MLL complex in castration-resistant prostate cancer [expression]. Homo sapiens

Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer. Overall design: ASH2L / Menin / MLL1 were knocked down using shRNA /siRNA in two prostate cancer cell lines, VCaP and LNCaP.

雄激素剥夺疗法抵抗与雄激素受体（androgen receptor, AR）活性升高，是去势抵抗性前列腺癌（castration-resistant prostate cancer, CRPC）的核心驱动因素。既往研究多聚焦于直接靶向AR，但AR信号通路共激活因子的识别与靶向仍属于未被充分探索的领域。本研究证实，混合谱系白血病（mixed-lineage leukemia, MLL）复合物——在MLL融合阳性白血病中已被广泛确认的致病关键因子——可作为AR信号通路的共激活因子。AR通过其亚基menin与MLL复合物发生特异性相互作用。小分子抑制menin与MLL的相互作用可阻断AR信号通路，并在体内抑制肿瘤生长。此外，本研究发现menin在CRPC组织中表达上调，且其高表达与患者不良总生存期显著相关。本研究确立MLL复合物作为AR的共激活因子，可作为晚期前列腺癌的潜在治疗靶点。实验整体设计：在VCaP与LNCaP两种前列腺癌细胞系中，通过shRNA/siRNA分别敲低ASH2L、Menin及MLL1的表达。