FOXM1 plays a role in autophagy by transcriptionally regulating Beclin-1 and LC3 genes in human triple-negative breast cancer cells

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 97; no. 4; pp. 491 - 508
• Main Authors: Hamurcu, Zuhal, Delibaşı, Nesrin, Nalbantoglu, Ufuk, Sener, Elif Funda, Nurdinov, Nursultan, Tascı, Bayram, Taheri, Serpil, Özkul, Yusuf, Donmez-Altuntas, Hamiyet, Canatan, Halit, Ozpolat, Bulent
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2019; Springer Nature B.V
• Subjects: Autophagy; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cell survival; Chromatin; Clinical trials; Drug resistance; Forkhead protein; Human Genetics; Immunoprecipitation; Internal Medicine; Medical prognosis; Molecular Medicine; Molecular modelling; Original Article; Phagocytosis; Proteins; Rapamycin; Starvation; Therapeutic applications; Transcription; Tumorigenesis; Beclin-1; FOXM1; Autophagy; LC3; Triple-negative breast cancer
• DOI: 10.1007/s00109-019-01750-8
• EISSN: 1432-1440
• ISSN: 0946-2716

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.