The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

Abstract

Protein ubiquitination is a critical regulator of cellular homeostasis. Aberrations in the addition or removal of ubiquitin can result in the development of cancer and key components of the ubiquitination machinery serve as oncogenes or tumour suppressors. An emerging target in the development of cancer therapeutics are the deubiquitinase (DUB) enzymes that remove ubiquitin from protein substrates. Whether this class of enzyme plays a role in cervical cancer has not been fully explored. By interrogating the cervical cancer data from the TCGA consortium, we noted that the DUB USP13 is amplified in ~15% of cervical cancer cases. We confirmed that USP13 expression was increased in cervical cancer cell lines, cytology samples from patients with cervical disease and in cervical cancer tissue. Depletion of USP13 inhibited cervical cancer cell proliferation. Mechanistically, USP13 bound to, deubiquitinated and stabilised Mcl-1, a pivotal member of the anti-apoptotic BCL-2 family. Furthermore, reduced Mcl-1 expression partially contributed to the observed proliferative defect in USP13 depleted cells. Importantly, the expression of USP13 and Mcl-1 proteins correlated in cervical cancer tissue. Finally, we demonstrated that depletion of USP13 expression or inhibition of USP13 enzymatic activity increased the sensitivity of cervical cancer cells to the BH3 mimetic inhibitor ABT-263. Together, our data demonstrates that USP13 is a potential oncogene in cervical cancer that functions to stabilise the pro-survival protein Mcl-1, offering a potential therapeutic target for these cancers.

Engineered Exosomes-Mediated Transfer of hsa-miR-320a Overcomes Chemoresistance in Cervical Cancer Cells via Targeting MCL1

“…MCL1, a pro-survival and pro-proliferative factor, plays a critical role in many tumor types. The deubiquitination and stabilisation of MCL1 was considered to be required for the proliferation of CC cells ( Morgan et al, 2021 ). What’s more, MCL1 siRNA-silencing demonstrated high efficacy on CC cell lines ( Lechanteur et al, 2017 ).…”

USP13 Genetics and Expression in a Family With Thyroid Cancer

“…On an opposite direction, other studies show that USP13 may act as an oncogene. For instance, USP13 stabilizes c-Myc that leads to an increased proliferation of glioma cells ( 14) and Mcl-1, which seems to increase proliferation of lung, ovarian and cervical cancer cells (13,31). Moreover, silencing USP13 decreased cell proliferation in lung metastasis of hepatocellular carcinoma (32) and its overexpression is correlated with poor prognosis and chemoresistance of ovarian cancer (33).…”

“…USP13 belongs to the USPs and its function in cancer is controversial. A recent study showed that USP13 may act as an oncogene in cervical cancer (13). In the same direction, it has been shown a pro-tumor role of USP13 in glioblastoma (14).…”

A Novel Mcl-1 Inhibitor Synergizes with Venetoclax to Induce Apoptosis in Cancer Cells

“…Mcl-1 has a short half-life and its expression is regulated by a variety of survival signals [28]. Multiple E3 ligases and deubiquitinases have been identi ed to control ubiquitination and proteasome mediated degradation of Mcl-1 [29][30][31][32]. In addition, Mcl-1 is structurally different from other Bcl-2 anti-apoptotic members at the long amino terminus, which contains two PEST domains, rich in proline(P), glutamic acid(E), serine(S) and threonine(E) amino-acid residues [24].…”