Faculty of Medicine, Department of Medical Biology, Erciyes University, Kayseri, Turkey.
Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey.
J Mol Med (Berl). 2019 Apr;97(4):491-508. doi: 10.1007/s00109-019-01750-8. Epub 2019 Feb 7.
Triple-negative breast cancer (TNBC) is associated with poor prognosis owing to its aggressive and heterogeneous nature, and the lack of therapeutic targets. Although Forkhead Box M1 (FOXM1) is one of the most important oncogenes contributing to tumorigenesis, progression, and drug resistance in TNBC, the underlying molecular mechanisms are not well understood. Emerging evidence indicates that autophagy plays a critical role in cell survival and protective mechanism in TNBC. However, signaling pathways that are involved in the regulation of autophagy remain to be elucidated. In the present study, we examined the role of FOXM1 in regulating autophagy in TNBC cells and found that FOXM1 is upregulated during induction of autophagy. We found that inhibition of FOXM1 suppressed starvation and rapamycin-induced autophagy and expression of the major autophagy regulators, LC3 and Beclin-1. Further studies demonstrated that FOXM1 directly binds to the promotors of LC3 and Beclin-1 genes and transcriptionally regulates their expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. In conclusion, our study provides the first evidence about the role of FOXM1 in regulating expression of LC3 and Beclin-1 and autophagy in TNBC cells. Our findings provide novel insight into the role of FOXM1 regulation of the autophagic survival pathway and potential molecular target for treating TNBC. KEY MESSAGES: • FOXM1 promotes tumorigenesis and progression of TNBC. However, the underlying molecular mechanism by which FOXM1 promotes TNBC tumorigenesis is unclear. The goal of our study was to determine the role of FOXM1 in the regulation of autophagy that plays a role in TNBC progression. Our findings show that FOXM1 binds to promoters of the genes encoding the major autophagy proteins, Beclin and LC3, and provide new insights into the regulation of autophagy, which is being targeted in many clinical trials.
三阴性乳腺癌（TNBC）由于其侵袭性和异质性以及缺乏治疗靶点，预后不良。尽管叉头框 M1（FOXM1）是导致 TNBC 肿瘤发生、进展和耐药性的最重要的癌基因之一，但潜在的分子机制尚不清楚。新出现的证据表明，自噬在 TNBC 中细胞存活和保护机制中发挥着关键作用。然而，参与自噬调节的信号通路仍有待阐明。在本研究中，我们研究了 FOXM1 在调节 TNBC 细胞自噬中的作用，发现自噬诱导时 FOXM1 上调。我们发现，FOXM1 抑制抑制饥饿和雷帕霉素诱导的自噬以及主要自噬调节剂 LC3 和 Beclin-1 的表达。进一步的研究表明，FOXM1 直接与 LC3 和 Beclin-1 基因的启动子结合，并通过染色质免疫沉淀（ChIP）和荧光素酶基因报告基因测定转录调节其表达。总之，本研究首次证明了 FOXM1 在调节 TNBC 细胞中 LC3 和 Beclin-1 和自噬的表达中的作用。我们的研究结果为 FOXM1 调节自噬存活途径提供了新的见解，并为治疗 TNBC 提供了潜在的分子靶点。关键信息：• FOXM1 促进 TNBC 的发生和发展。然而，FOXM1 促进 TNBC 发生的潜在分子机制尚不清楚。我们研究的目的是确定 FOXM1 在调节自噬中的作用，自噬在 TNBC 进展中起作用。我们的研究结果表明，FOXM1 结合到编码主要自噬蛋白 Beclin 和 LC3 的基因启动子上，并为自噬的调节提供了新的见解，自噬正在许多临床试验中作为靶点。
