Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner
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Mcl-1 is a unique Bcl-2 family member that plays crucial roles in apoptosis. Apoptosis-unrelated functions of Mcl-1 are however emerging, further justifying its tight regulation. Here we unravel a novel mechanism of Mcl-1 regulation mediated by the haplo-insufficient tumour suppressor Beclin 1. Beclin 1 negatively modulates Mcl-1 stability in a reciprocal manner whereby depletion of one leads to the stabilization of the other. This co-regulation is independent of autophagy and of their physical interaction. Both Beclin 1 and Mcl-1 are deubiquitinated and thus stabilized by binding to a common deubiquitinase, USP9X. Beclin 1 and Mcl-1 negatively modulate the proteasomal degradation of each other through competitive displacement of USP9X. The analysis of patient-derived melanoma cells and tissue samples shows that the levels of Beclin 1 decrease, while Mcl-1 levels subsequently increase during melanoma progression in a significant inter-dependent manner. The identified inverse co-regulation of Beclin 1 and Mcl-1 represents a mechanism of functional counteraction in cancer.
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Other tumor-promoting roles of MCL-1 in autophagy and cellular bioenergetics are emerging.
“other tumor-promoting roles in autophagy and cellular bioenergetics are emerging (Elgendy, 2017; Elgendy et al., 2014, 2017; Elgendy and Minucci, 2015; Perciavalle et al., 2012).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Elgendy et al., 2014
The primary melanoma cell lines GaLa1949 and LuCa1970 were established from metastatic melanoma samples as described in an earlier publication.
“Establishment of primary cells GaLa1949 and LuCa1970 from metastatic melanomas was previously described in (Elgendy et al., 2014).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Elgendy et al., 2014
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References 37 · Cited by 83
- Authors
- Elgendy, M., Ciro, M., Abdel-Aziz, A. K., Belmonte, G., Zuffo, R. D., Mercurio, C., Miracco, C., Lanfrancone, L., Foiani, M., & Minucci, S.
- Affiliations
- European Institute of Oncology (IT)
- University of Siena (IT)
- University of Milan (IT)
- Corresponding author
- Minucci, Saverio
- Venue
- Nature Communications
- Published
- 2014-12-04
- Volume
- 5
- Issue
- 1
- Pages
- 5637-5637
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2017326383
- Cited by
- 83
- References
- 37
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 12 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 7
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Use Siena air (University of Siena) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro
- Regione Lombardia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Beclin-1, Mcl-1, USP9X, deubiquitination, protein stability, carcinogenesis, melanoma progression, tumour suppressor, Bcl-2 family proteins, proteasomal degradation, protein-protein competition
- MeSH terms
- Beclin-1, Animals, Autophagy, HeLa Cells, Humans, Melanoma, Membrane Proteins, Neoplasm Transplantation, Skin Neoplasms, Tumor Cells, Cultured, Ubiquitin Thiolesterase, Apoptosis Regulatory Proteins, Mice, HEK293 Cells, Haploinsufficiency, Carcinogenesis, Myeloid Cell Leukemia Sequence 1 Protein
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