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

Author

Listed:
  • Mohamed Elgendy

    (European Institute of Oncology, IEO)

  • Marco Ciro

    (European Institute of Oncology, IEO
    IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) at the IFOM–European Institute of Oncology (IEO) Campus)

  • Amal Kamal Abdel-Aziz

    (European Institute of Oncology, IEO
    Present address: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt)

  • 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
    University of Milan)

  • Saverio Minucci

    (European Institute of Oncology, IEO
    University of Milan
    Drug Development Program, European Institute of Oncology, IEO)

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.

Suggested Citation

  • Mohamed Elgendy & Marco Ciro & Amal Kamal Abdel-Aziz & Giuseppe Belmonte & Roberto Dal Zuffo & Ciro Mercurio & Clelia Miracco & Luisa Lanfrancone & Marco Foiani & Saverio Minucci, 2014. "Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6637
    DOI: 10.1038/ncomms6637
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