Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Abstract

MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin-proteasome system in clinical practice.

Fig. 1. Schematic model of MCL1 protein.

MCL1 contains a long N-terminal regulatory domain harboring a PEST sequence, BH1–BH4 motifs and a C-terminal transmembrane (TM) domain. The arrows indicate the sites of ubiquitination (Ub): K48-linked polyubiquitin chains (red) and K63-linked polyubiquitin chains (green).

Fig. 2. The role of MCL1 in mitochondrial apoptotic signaling.

MCL1 interacts with and sequesters proapoptotic proteins to suppress mitochondrial outer membrane permeabilization (MOMP) and cytochrome c (Cyt C) release to exert its pro-survival effects.

Fig. 3. E3 ligases and deubiquitinases balance MCL1 stability.

E3 ligases (Mule, SCF^β-TrCP, SCF^FBW7, TRIM17, APC/C^Cdc20, and FBXO4) promote the ubiquitination and degradation of MCL1, whereas deubiquitinases (USP9X, Ku70, USP13, JOSD1, and DUB3) deubiquitinate MCL1 to prevent its degradation.

Fig. 4. Strategies for targeting MCL1.

a Inhibitors specifically bind to MCL1, preventing its binding and inhibition of BAX and BAK, and leading to activation of mitochondrial apoptotic signaling. b Inhibitors indirectly suppress MCL1 by targeting transcriptional regulators of MCL1. c Inhibitors or RNAi indirectly suppress MCL1 by targeting MCL1 DUBs. d PROTAC strategy via recruitment of the CUL4A–DDB1 complex to facilitate ubiquitination-mediated degradation of MCL1 protein.