1. Academic Validation
  2. Interplay between protein acetylation and ubiquitination controls MCL1 protein stability

Interplay between protein acetylation and ubiquitination controls MCL1 protein stability

  • Cell Rep. 2021 Nov 9;37(6):109988. doi: 10.1016/j.celrep.2021.109988.
Kouhei Shimizu 1 Min Gi 2 Shugo Suzuki 3 Brian J North 4 Asami Watahiki 5 Satoshi Fukumoto 6 John M Asara 7 Fuminori Tokunaga 8 Wenyi Wei 9 Hiroyuki Inuzuka 10
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan; Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan. Electronic address: [email protected].
  • 2 Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
  • 3 Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
  • 4 Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA.
  • 5 Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
  • 6 Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan; Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan; Section of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka 812-8582, Japan.
  • 7 Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 8 Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
  • 9 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
  • 10 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
Abstract

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.

Keywords

MCL1; USP9X; acetylation; chemoresistance; p300; protein degradation; protein stability; ubiquitination.

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