Saltar al contenido
Merck

Interplay between protein acetylation and ubiquitination controls MCL1 protein stability.

Cell reports (2021-11-11)
Kouhei Shimizu, Min Gi, Shugo Suzuki, Brian J North, Asami Watahiki, Satoshi Fukumoto, John M Asara, Fuminori Tokunaga, Wenyi Wei, Hiroyuki Inuzuka
RESUMEN

The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. Here, we identify acetylation as another critical post-translational modification regulating MCL1 protein stability. We demonstrate that the lysine acetyltransferase p300 targets MCL1 at K40 for acetylation, which is counteracted by the deacetylase sirtuin 3 (SIRT3). Mechanistically, acetylation enhances MCL1 interaction with USP9X, resulting in deubiquitination and subsequent MCL1 stabilization. Therefore, ectopic expression of acetylation-mimetic MCL1 promotes apoptosis evasion of cancer cells, enhances colony formation potential, and facilitates xenografted tumor progression. We further demonstrate that elevated MCL1 acetylation sensitizes multiple cancer cells to pharmacological inhibition of USP9X. These findings reveal that acetylation of MCL1 is a critical post-translational modification enhancing its oncogenic function and provide a rationale for developing innovative therapeutic strategies for MCL1-dependent tumors.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
ANTI-FLAG® M2 monoclonal antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Anti-α-tubulina monoclonal antibody produced in mouse, ascites fluid, clone B-5-1-2
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Trichostatin A, ≥98% (HPLC), from Streptomyces sp.
Sigma-Aldrich
Cicloheximida, Biotechnology Performance Certified
Sigma-Aldrich
IgG anti-conejo (molécula completa)-Peroxidasa antibody produced in goat, affinity isolated antibody, buffered aqueous solution