The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the BCL2 family that supports survival and is frequently amplified or upregulated in human cancers. MCL1 is highly unstable and its stability is regulated by phosphorylation and ubiquitination. Here, the authors suggest that acetylation is another key post-translational modification that regulates MCL1 protein instability. The authors demonstrated that the lysine acetyltransferase p300 targets K40 of MCL1 for acetylation, which is counteracted by the deacetylase sirtuin3 (SIRT3).
Myeloid cell leukemia 1 (Mcl1), a member of the anti-apoptotic bcl2 family, is an important pro-apoptotic factor that plays a key role in inhibiting apoptosis mainly by inhibiting the activity of pro-apoptotic bcl2 family proteins or pro-apoptotic bh-3 proteins. Overexpression or amplification of MCL1 is common in multiple cancer types and is therefore considered to be one of the most relevant oncoproteins. Due to its key pro-survival activity, upregulation of mcl1 largely contributes to the development of chemoresistance. Therefore, understanding the precise molecular mechanisms underlying the regulation of MCL1 oncogenic activity is important for finding effective antitumor therapeutics and improving chemosensitivity.
The abundance of MCL1 protein is tightly controlled by transcriptional, post-transcriptional, translational and post-translational mechanisms. Accumulating evidence suggests that multiple growth factors and cytokines induce mcl1 gene expression, multiple microRNAs and lncRNAs control the stability of mcl1 mRNA, and mTORC1 promotes the translation of mcl1 protein. As a unique property, MCL1 protein is very unstable compared to other anti-apoptotic BCL2 family members.
Thus, rapid degradation of mcl1 may provide a mechanism by which cells rapidly commit to apoptosis in response to various intrinsic or extracellular signals. Mechanistically, MCL1 has a unique extended N-terminal region that contains a proline/glutamic acid/serine/threonine (PEST) rich sequence, a common motif in unstable proteins with short protein half-lives. Previous studies have shown that the MCL1PEST sequence contains multiple phosphorylation sites affecting MCL1 ubiquitination. In support of these observations, the stability of mcl1 protein is tightly controlled by ubiquitination, which is achieved through the activity of multiple upstream E3 ubiquitin ligases.
Acetylation is a fundamental type of lysine modification, which controls a variety of biological processes, including protein-protein interactions, transcription, subcellular localization, and enzymatic activity of numerous proteins. In addition, many acetylated targeted non-histone proteins are oncoproteins or tumor suppressors, which are directly involved in tumor initiation, progression and metastasis.
In this study, the authors demonstrated that MCL1 is acetylated by p300, resulting in MCL1 ubiquitination and subsequent reduced MCL1 protein stability, which is counteracted by sirtuin 3 (SIRT3). The enhanced interaction of USP9X with acetylated MCL1 may be a potential molecular mechanism for acetylation-dependent MCL1 stabilization.
In a xenograft mouse model, the authors further confirmed that MCL1 acetylation affects apoptotic evasion of cancer cells and promotes tumor progression. These findings suggest that MCL1 acetylation plays a crucial role in tumor cell survival and acquired chemoresistance, which provides insight into targeting acetylated MCL1 as a potential therapeutic intervention.