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

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Abstract

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.

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Abbreviations

TNBC:

Triple-negative breast cancer

FOXM1:

Forkhead Box M1

LC3:

Microtubule-associated light chain 3

ChIP:

Chromatin immunoprecipitation

ER:

Estrogen receptors

HR:

Hormone receptors

HER2:

Human epidermal growth factor receptor 2

PR:

Progesterone receptor

eEF2K:

Eukaryotic elongation factor 2 kinase

RT-PCR:

Reverse transcriptase and polymerase chain reaction

AVOs:

Acidic vesicular organelles

Atg:

Autophagy-related genes

siRNAs:

Small interfering RNAs

BS:

Binding sites

PBS:

Phosphate-buffered saline

TBST:

Tris-buffered saline–Tween 20

cDNA:

Complementary DNA

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Funding

This study was funded by The Scientific and Technological Research Council –TÜBİTAK- research grant (grant number 214S204) and Research Fund of the Erciyes University (Project number: TDA-2016-6415).

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Authors and Affiliations

  1. Faculty of Medicine, Department of Medical Biology, Erciyes University, Kayseri, Turkey

    Zuhal Hamurcu, Nesrin Delibaşı, Elif Funda Sener, Nursultan Nurdinov, Serpil Taheri, Hamiyet Donmez-Altuntas & Halit Canatan

  2. Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey

    Zuhal Hamurcu, Nesrin Delibaşı, Ufuk Nalbantoglu, Elif Funda Sener, Nursultan Nurdinov, Bayram Tascı, Serpil Taheri & Yusuf Özkul

  3. Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Zuhal Hamurcu & Bulent Ozpolat

  4. Faculty of Engineering, Department of Computer Engineering, Bioinformatics, Genome and Stem Cell Center, Kayseri, Turkey

    Ufuk Nalbantoglu

  5. Medical Faculty, Erciyes University, Kayseri, Turkey

    Bayram Tascı

  6. Faculty of Medicine, Department of Medical Genetics, Erciyes University, Kayseri, Turkey

    Yusuf Özkul

  7. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA

    Bulent Ozpolat

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  1. Zuhal Hamurcu
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  2. Nesrin Delibaşı
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  11. Bulent Ozpolat
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Correspondence to Bulent Ozpolat.

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Hamurcu, Z., Delibaşı, N., Nalbantoglu, U. et al. FOXM1 plays a role in autophagy by transcriptionally regulating Beclin-1 and LC3 genes in human triple-negative breast cancer cells. J Mol Med 97, 491–508 (2019). https://doi.org/10.1007/s00109-019-01750-8

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