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The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer
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The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer
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Journal Article
The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/95
/ 42/89
/ 96/1
/ 96/109
/ 96/2
/ Aniline Compounds - pharmacology
/ Cell Proliferation - drug effects
/ Cervix
/ Cytology
/ Deubiquitinating Enzymes - genetics
/ Female
/ Humans
/ Medicine
/ Myeloid Cell Leukemia Sequence 1 Protein - genetics
/ Oncology
/ Protein Stability - drug effects
/ Proteins
/ Tumors
/ Ubiquitin-Specific Proteases - genetics
/ Uterine Cervical Neoplasms - drug therapy
