title: Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgendy
authors.affiliation: 1] Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy [2] IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) at the IFOM-European Institute of Oncology (IEO) Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ciro
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Amal Kamal
authors.initials: AK
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belmonte
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dal Zuffo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, 53100 Siena, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Miracco
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lanfrancone
authors.affiliation: 1] IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) at the IFOM-European Institute of Oncology (IEO) Campus, Via Adamello 16, 20139 Milan, Italy [2] Department of Biosciences, University of Milan, 20100 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Foiani
authors.affiliation: 1] Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy [2] Department of Biosciences, University of Milan, 20100 Milan, Italy [3] Drug Development Program, European Institute of Oncology, IEO, 20139 Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D063646:Carcinogenesis; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C506234:USP9X protein, human; D043222:Ubiquitin Thiolesterase