Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, USA.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Nat Genet. 2020 Oct;52(10):1011-1017. doi: 10.1038/s41588-020-0681-7. Epub 2020 Aug 31.
FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor, 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), 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 作为先驱转录因子发挥作用，促进甾体激素受体（如雄激素受体和雌激素受体）与染色质的结合，但调节其与染色质结合的机制仍不清楚。LSD1（KDM1A）通过去甲基化单/二甲基化组蛋白 H3 赖氨酸 4（H3K4me1/2）作为转录抑制因子发挥作用，但也通过尚不清楚的机制作为甾体激素受体辅激活因子发挥作用。在这里，我们在前列腺癌细胞中表明，LSD1 与 FOXA1 和活性增强子标记物相关联，并且 LSD1 抑制会全局破坏 FOXA1 染色质结合。在机制上，我们证明 LSD1 通过去甲基化赖氨酸 270（FOXA1 DNA 结合域的 wing2 区域附近）来正向调节 FOXA1 结合。通过 FOXA1，LSD1 抑制广泛破坏了雄激素受体结合及其转录产物，并且单独和与雄激素受体拮抗剂治疗在体内协同作用时显著降低了前列腺癌的生长。这些机制上的见解为甾体驱动的癌症提供了新的治疗策略。
