Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner
Elgendy, Mohamed; Ciro, Marco; Abdel-Aziz, Amal Kamal; Belmonte, Giuseppe; Dal Zuffo, Roberto; Mercurio, Ciro; Miracco, Clelia; Lanfrancone, Luisa; Foiani, Marco; Minucci, Saverio;
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.
Other data
Title | Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner | Authors | Elgendy, Mohamed; Ciro, Marco; Abdel-Aziz, Amal Kamal ; Belmonte, Giuseppe; Dal Zuffo, Roberto; Mercurio, Ciro; Miracco, Clelia; Lanfrancone, Luisa; Foiani, Marco; Minucci, Saverio | Keywords | TARGETING MCL-1; PROSTATE-CANCER; MELANOMA-CELLS; APOPTOSIS; EXPRESSION; RESISTANCE; SURVIVAL; THERAPY; INHIBITION; SABUTOCLAX | Issue Date | 4-Dec-2014 | Publisher | NATURE PUBLISHING GROUP | Journal | Nature communications | ISSN | 2041-1723 | DOI | 10.1038/ncomms6637 | PubMed ID | 25472497 | Scopus ID | 2-s2.0-84923378545 | Web of science ID | WOS:000347226900007 |
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