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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Apoptosis
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Stability*
  • Tumor Cells, Cultured
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination*
  • Xenograft Model Antitumor Assays
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • USP9X protein, human
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Ubiquitin Thiolesterase