FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor^1,2,3,4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)^5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.

FOXA1 通过促进类固醇激素受体（如雄激素受体和雌激素受体^1,2,3,4 ）进入染色质而发挥先锋转录因子的作用，但调节其与染色质结合的机制仍然难以捉摸。^{LSD1 (KDM1A) 通过去甲基化单/二甲基化组蛋白 H3 赖氨酸 4 (H3K4me1/2) 5,6}作为转录阻遏物，但也通过尚不清楚的机制充当类固醇激素受体共激活剂。在这里，我们显示，在前列腺癌细胞中，LSD1 与 FOXA1 和活性增强子标志物相关，并且 LSD1 抑制在全球范围内破坏了 FOXA1 染色质的结合。从机制上讲，我们证明 LSD1 通过将邻近 FOXA1 DNA 结合域的wing2 区域的赖氨酸 270 去甲基化来正调节 FOXA1 结合。通过 FOXA1，LSD1 抑制广泛地破坏了雄激素受体结合及其转录输出，并在体内单独和与雄激素受体拮抗剂治疗协同作用时显着降低了前列腺癌的生长。这些机制见解为类固醇驱动的癌症提出了新的治疗策略。