Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

Mohamed Elgendy, Marco Ciro, Amal Kamal Abdel-Aziz, Giuseppe Belmonte, Roberto Dal Zuffo, Ciro Mercurio, Clelia Miracco, Luisa Lanfrancone, Marco Foiani and Saverio Minucci ()
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Mohamed Elgendy: European Institute of Oncology, IEO
Marco Ciro: European Institute of Oncology, IEO
Amal Kamal Abdel-Aziz: European Institute of Oncology, IEO
Giuseppe Belmonte: University of Siena
Roberto Dal Zuffo: European Institute of Oncology, IEO
Ciro Mercurio: European Institute of Oncology, IEO
Clelia Miracco: University of Siena
Luisa Lanfrancone: European Institute of Oncology, IEO
Marco Foiani: IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) at the IFOM–European Institute of Oncology (IEO) Campus
Saverio Minucci: European Institute of Oncology, IEO

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6637

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