Resumen
Triple-negative breast cancer (TNBC) poses significant challenges for treatment given the lack of targeted therapies and increased probability of relapse. It is pertinent to identify vulnerabilities in TNBC and develop newer treatments. Our prior research demonstrated that transcription factor EB (TFEB) is necessary for TNBC survival by regulating DNA repair, apoptosis signaling, and the cell cycle. However, specific mechanisms by which TFEB targets DNA repair and cell cycle pathways are unclear, and whether these effects dictate TNBC survival is yet to be determined. Here, we show that TFEB knockdown decreased the expression of genes and proteins involved in DNA replication and cell cycle progression in MDA-MB-231 TNBC cells. DNA replication was decreased in cells lacking TFEB, as measured by EdU incorporation. TFEB silencing in MDA-MB-231 and noncancerous MCF10A cells impaired progression through the S-phase following G1/S synchronization; however, this proliferation defect could not be rescued by co-knockdown of suppressor RB1. Instead, TFEB knockdown reduced origin licensing in G1 and early S-phase MDA-MB-231 cells. TFEB silencing was associated with replication stress in MCF10A but not in TNBC cells. Lastly, we identified that TFEB knockdown renders TNBC cells more sensitive to inhibitors of Aurora Kinase A, a protein facilitating mitosis. Thus, inhibition of TFEB impairs cell cycle progress by decreasing origin licensing, leading to delayed entry into the S-phase, while rendering TNBC cells sensitive to Aurora kinase A inhibitors and decreasing cell viability. In contrast, TFEB silencing in noncancerous cells is associated with replication stress and leads to G1/S arrest.
Idioma original | English |
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Número de artículo | 102692 |
Publicación | Journal of Biological Chemistry |
Volumen | 298 |
N.º | 12 |
DOI | |
Estado | Published - dic. 2022 |
Nota bibliográfica
Funding Information:This work was funded by grants to T. P from the NSERC (RGPIN-2020–05906), Diabetes Canada (NOD_OG-3-15–5037-TP, NOD_SC-5-16–5054-TP), and the New Brunswick Health Research Foundation. L. S. is funded by a doctoral Alexander Graham Bell Canada Graduate Scholarship from NSERC and the Killam pre-doctoral scholarship. D. B. is funded by Postdoctoral fellowships from the New Brunswick Health Research Foundation. T. P. is a Diabetes Canada Scholar.
Publisher Copyright:
© 2022 The Authors
ASJC Scopus Subject Areas
- Biochemistry
- Molecular Biology
- Cell Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't