Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2020 Jan 23;11(1):441. doi: 10.1038/s41467-020-14318-9.
Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.
前列腺癌是全球男性中第二大常见的恶性肿瘤。FOXA1 在原发性和转移性前列腺肿瘤中经常发生突变，它编码一种先驱转录因子，通过雄激素受体依赖性和非依赖性机制参与疾病的发生和进展。然而，尽管具有致癌特性，但 FOXA1 表达的调控仍不清楚。在这里，我们在 FOXA1 调控丛中鉴定了一组六个顺式调控元件，这些元件在原发性前列腺肿瘤中存在体细胞单核苷酸变异。我们发现，这些顺式调控元件的缺失和抑制会显著降低 FOXA1 的表达和前列腺癌细胞的生长。映射到 FOXA1 调控丛的十个单核苷酸变异中的六个通过调节转录因子的结合显著改变了顺式调控元件的转录激活潜力。总的来说，我们的研究结果确定了原发性前列腺肿瘤中 FOXA1 丛内的顺式调控元件作为潜在治疗靶点。
