Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.
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.
Apoptosis‐inducing factor (AIF) plays a dual role in regulating cell survival and apoptosis, acting as a prosurvival factor in mitochondria via its NADH oxidoreductase activity and activating the caspase‐independent apoptotic pathway (i.e., parthanatos) after nuclear translocation. However, whether one factor conjunctively controls the separated functions of AIF is not clear. Here, it is shown that OTU deubiquitinase 1 (OTUD1) acts as a link between the two functions of AIF via deubiquitination events. Deubiquitination of AIF at K244 disrupts the normal mitochondrial structure and compromises oxidative phosphorylation, and deubiquitination of AIF at K255 enhances its DNA‐binding ability to promote parthanatos. Moreover, OTUD1 stabilizes DDB1 and CUL4 associated factor 10 (DCAF10) and recruits the cullin 4A (CUL4A)‐damage specific DNA binding protein 1 (DDB1) complex to promote myeloid cell leukemia sequence 1 (MCL1) degradation, thereby activating caspase‐dependent apoptotic signaling. Collectively, these results reveal the central role of OTUD1 in activating both caspase‐independent and caspase‐dependent apoptotic signaling and propose decreased OTUD1 expression as a key event promoting chemoresistance in esophageal squamous cell carcinoma.
Highlights d ARID1A stability is controlled by the ubiquitin-proteasome system d TRIM32 promotes squamous cell carcinoma progression by degrading ARID1A d USP11 prevents squamous cell carcinoma progression by stabilizing ARID1A d ARID1A loss activates SDC2 to drive squamous cell carcinoma development
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