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Journal of Molecular Medicine

, Volume 97, Issue 4, pp 491–508 | Cite as

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

  • Zuhal Hamurcu
  • Nesrin Delibaşı
  • Ufuk Nalbantoglu
  • Elif Funda Sener
  • Nursultan Nurdinov
  • Bayram Tascı
  • Serpil Taheri
  • Yusuf Özkul
  • Hamiyet Donmez-Altuntas
  • Halit Canatan
  • Bulent OzpolatEmail author
Original Article

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.

Keywords

Autophagy Beclin-1 FOXM1 LC3 Triple-negative breast cancer 

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

109_2019_1750_MOESM1_ESM.pptx (663 kb)
ESM 1 (PPTX 663 kb)
109_2019_1750_MOESM2_ESM.pptx (61 kb)
ESM 2 (PPTX 60 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Zuhal Hamurcu
    • 1
    • 2
    • 3
  • Nesrin Delibaşı
    • 1
    • 2
  • Ufuk Nalbantoglu
    • 2
    • 4
  • Elif Funda Sener
    • 1
    • 2
  • Nursultan Nurdinov
    • 1
    • 2
  • Bayram Tascı
    • 2
    • 5
  • Serpil Taheri
    • 1
    • 2
  • Yusuf Özkul
    • 2
    • 6
  • Hamiyet Donmez-Altuntas
    • 1
  • Halit Canatan
    • 1
  • Bulent Ozpolat
    • 3
    • 7
    Email author
  1. 1.Faculty of Medicine, Department of Medical BiologyErciyes UniversityKayseriTurkey
  2. 2.Betül-Ziya Eren Genome and Stem Cell CenterErciyes UniversityKayseriTurkey
  3. 3.Center for RNA Interference and Non-Coding RNAThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Faculty of Engineering, Department of Computer EngineeringBioinformatics, Genome and Stem Cell CenterKayseriTurkey
  5. 5.Medical FacultyErciyes UniversityKayseriTurkey
  6. 6.Faculty of Medicine, Department of Medical GeneticsErciyes UniversityKayseriTurkey
  7. 7.Department of Experimental TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonUSA

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