**4. DUBs and Apoptosis**

The ability to evade apoptosis is one of the essential changes in cancer cells that causes malignant transformation [111]. Apoptosis is a cellular self-destruction program in response to various cellular stresses. The two extrinsic and intrinsic pathways in apoptosis both involve the activation of caspase molecules. The activation of initiator caspase will further lead to the activation of executioner caspase

in apoptosis [112]. DUBs were found to target di fferent pro- and anti-apoptotic proteins in both the extrinsic and intrinsic pathways. ATXN3 stabilizes p53 by deubiquitination and promotes p53-mediated apoptosis [61]. USP5 targets p53-unanchored UBQ polymers and regulates p53-mediated transcription. Depletion of USP5 controls tumor necrosis factor alpha apoptosis-inducing ligand (TRAIL)-mediated apoptotic responsiveness in TRAIL-resistant tumor cells, and this function of USP5 ubiquitination can be blocked by caspase 8-specific inhibitors [63]. In addition, USP5 deubiquitinates the MAF bZIP transcription factor and prevents its degradation. Knockdown of USP5 leads to apoptosis in multiple myeloma cells [64]. In a chemoresistant xenograft model, JOSD1 was identified to be upregulated during the development of chemoresistance. Moreover, JOSD1 has been reported to deubiquitinate and stabilize MCL1, which plays a suppressive role in mitochondrial apoptotic signaling. Therefore, depletion of JOSD1 leads to severe apoptosis in gynecological cancer cells through the degradation of MCL1 [62]. There are several DUBs that regulate the apoptotic pathways via BCL-2 family, an inhibitor of apoptotic proteins (IAPs) and caspases. DUB3/USP17 induces apoptosis through caspase 3 activation [113], whereas USP15 plays a role in stabilizing procaspse 3 [114]. Besides, A20, a DUB belongs to the OTU subclass, interacts with caspase 8 to reverse the ubiquitination of a cullin 3-based E3 ligase [115]. As for the IAPs, they are a class of proteins that inhibit apoptosis. They contain the baculovirus IAP repeat domain and the RING domain that provides the E3 ligase property [116]. USP19 stabilizes the cellular IAP1 and cellular IAP2 during caspase activation and apoptosis [117]; OTUD1 was found to regulate the TNF-dependent cell death by modulating the cellular IAP1 stability [118]. Furthermore, USP9X was reported to interact with an E3 ligase X-linked IAP for mitotic cell fate decision [119]. In addition, USP27X was found to interact with the BIM. BIM is a pro-apoptotic BH3-only protein that regulates the cell death proteins such as BAX. Overexpression of Usp27x reduces BIM ubiquitination, and induces apoptosis in tumor cells. On the other hand, suppression of USP27X could reduce apoptosis [120].
