The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer.
The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer.
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DOI：
10.1038/s41388-021-01679-8
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Macdonald A
中科院分区：
文献类型：
--
作者：
Morgan EL;Patterson MR;Barba-Moreno D;Scarth JA;Wilson A;Macdonald A
蛋白质泛素化是细胞稳态的重要调节因子。泛素添加或去除的异常可导致癌症的发展，泛素化机制的关键成分可作为癌基因或肿瘤抑制因子。在癌症治疗的发展中，一个新兴的目标是去泛素酶（DUB）酶，它可以从蛋白质底物中去除泛素。这类酶是否在宫颈癌中起作用还没有得到充分的探讨。通过查询TCGA联盟的宫颈癌数据，我们注意到DUB USP13在约15%的宫颈癌病例中扩增。我们证实，USP13在宫颈癌细胞系、宫颈疾病患者细胞学样本和宫颈癌组织中的表达增加。缺失USP13抑制子宫颈癌细胞增殖。机制上，USP13结合，去泛素化和稳定Mcl-1，抗凋亡BCL-2家族的关键成员。此外，Mcl-1表达的降低部分促成了USP13缺失细胞中观察到的增殖缺陷。重要的是，USP13和Mcl-1蛋白的表达在宫颈癌组织中是相关的。最后，我们证明了USP13表达的缺失或USP13酶活性的抑制增加了宫颈癌细胞对BH3模拟抑制剂ABT-263的敏感性。总之，我们的数据表明，USP13是宫颈癌的潜在致癌基因，其功能是稳定促生存蛋白Mcl-1，为这些癌症提供潜在的治疗靶点。
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.
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影响因子：
11.2
作者：
Chen S;Dai Y;Pei XY;Myers J;Wang L;Kramer LB;Garnett M;Schwartz DM;Su F;Simmons GL;Richey JD;Larsen DG;Dent P;Orlowski RZ;Grant S
通讯作者：
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影响因子：
8.8
作者：
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影响因子：
6.4
作者：
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通讯作者：
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影响因子：
44.1
作者：
Huang X;Dixit VM
通讯作者：
Dixit VM
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影响因子：
6.4
作者：
Chen, Chen;Meng, Yan;Du, Jie
通讯作者：
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