Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.
Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Sci Rep. 2024 Mar 25;14(1):7082. doi: 10.1038/s41598-024-57854-w.
FOXA1 is a pioneer transcription factor that is frequently mutated in prostate, breast, bladder, and salivary gland malignancies. Indeed, metastatic castration-resistant prostate cancer (mCRPC) commonly harbour FOXA1 mutations with a prevalence of 35%. However, despite the frequent recurrence of FOXA1 mutations in prostate cancer, the mechanisms by which FOXA1 variants drive its oncogenic effects are still unclear. Semaphorin 3C (SEMA3C) is a secreted autocrine growth factor that drives growth and treatment resistance of prostate and other cancers and is known to be regulated by both AR and FOXA1. In the present study, we characterize FOXA1 alterations with respect to its regulation of SEMA3C. Our findings reveal that FOXA1 alterations lead to elevated levels of SEMA3C both in prostate cancer specimens and in vitro. We further show that FOXA1 negatively regulates SEMA3C via intronic cis elements, and that mutations in FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting DNA binding of FOXA1. Our findings underscore the key role of FOXA1 in prostate cancer progression and treatment resistance by regulating SEMA3C expression and suggest that SEMA3C may be a driver of growth and tumor vulnerability of mCRPC harboring FOXA1 alterations.
FOXA1 是一种先驱转录因子，在前列腺癌、乳腺癌、膀胱癌和唾液腺癌恶性肿瘤中经常发生突变。事实上，转移性去势抵抗性前列腺癌（mCRPC）通常携带有 FOXA1 突变，其患病率为 35%。然而，尽管 FOXA1 突变在前列腺癌中经常发生，但 FOXA1 变体驱动其致癌效应的机制仍不清楚。Sema 蛋白 3C（SEMA3C）是一种分泌的自分泌生长因子，可驱动前列腺癌和其他癌症的生长和治疗耐药性，并且已知其受 AR 和 FOXA1 的共同调控。在本研究中，我们针对 FOXA1 对 SEMA3C 的调控作用进行了特征描述。我们的研究结果表明，FOXA1 改变会导致前列腺癌标本和体外 SEMA3C 水平升高。我们进一步表明，FOXA1 通过内含子顺式元件负调控 SEMA3C，FOXA1 叉头结构域的突变会削弱其在报告基因检测中的抑制功能，推测是通过破坏 FOXA1 的 DNA 结合。我们的研究结果强调了 FOXA1 通过调节 SEMA3C 表达在前列腺癌进展和治疗耐药中的关键作用，并表明 SEMA3C 可能是携带 FOXA1 改变的 mCRPC 生长和肿瘤易感性的驱动因素。
