Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…118,119 The protein transportation, apoptosis, autophagy, cell growth and invasion are among biological mechanisms modulated by USP9X. [120][121][122] Recently, attention has been directed toward the role of USP9X in tumor cells. Overexpression of USP9X leads to cisplatin resistance of cancers and its suppression promotes drug sensitivity via inactivating βcatenin signaling.…”

Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it

“…This region of Mcl-1 is subject to ubiquitination by E3 ligases Mcl-1 ubiquitin ligase E3 (MULE) [ 32 ], Skp1, Cdc53/Cul1, F-box protein beta-transducin repeat containing protein (SCF β-TrCP ) [ 33 ], anaphase promoting complex/cyclosome-cell division cycle protein 20 homolog (APC/C cdc20 ) [ 34 ] and F-box and tryptophan-aspartic acid (WD) repeat-containing protein 7 (FBX FBW7 ) [ 35 ]. Mcl-1 is protected from proteasomal degradation by a deubiquitinase ubiquitin specific peptidase 9 X-linked (USP9X) which removes the ubiquitin chains conjugated onto the Mcl-1 ( Figure 1 ) [ 36 , 37 ]. Our recent studies have demonstrated the prognostic potential of USP9X in oral cancers.…”

“…We showed that its overexpression contributes to the stabilization of Mcl-1 protein from early to the late stages of oral tumorigenesis and also to therapy resistance leading to poor prognosis. Moreover, pharmacological inhibition of USP9X potently induced cell death in oral cancer cells through rapid degradation of Mcl-1 [ 37 ]. More recently, the deubiquitinases USP13 and USP7 have also been shown to contribute to Mcl-1 stabilization and drive tumorigenesis [ 38 , 39 ].…”

“…Since Mcl-1 protein is critical for survival, tumor cells maintain its sustained elevated levels partly through its posttranslational stabilization-deubiquitination. As the deubiquitinase USP9X is known to stabilize Mcl-1 [ 36 , 54 ], the deubiquitinase inhibitor WP1130 has been shown to induce apoptosis in a manner that involves potent Mcl-1 downregulation [ 37 , 99 ]. Apart from USP9X, USP13 [ 38 ] and USP7 [ 39 ] have been implicated in deubiquitination and thereby stabilization of Mcl-1 in various cancer settings.…”

“…Mcl-1 is protected from proteasomal degradation by a deubiquitinase ubiquitin specific peptidase 9 X-linked (USP9X) which removes the ubiquitin chains conjugated onto the Mcl-1 (Figure 1) [36,37]. Our recent studies have demonstrated the prognostic potential of USP9X in oral cancers.…”