E3 ligase HERC5-catalyzed UGDH isgylation promotes SNAI1-mediated tumor metastasis and cisplatin resistance in oral squamous cell carcinoma.

IF 5.7 2区 生物学 Q1 BIOLOGY
Xu Zhang, Fayu Liu, Qigen Fang, Changfu Sun, Jie Fan
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Abstract

Background: Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related mortality worldwide due to its high aggressive potential and drug resistance. Previous studies have revealed an important function of HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 5 (HERC5) in cancer. Six GEO gene microarrays identified HERC5 as a significant upregulated gene in OSCC tissues or cells (log2 Fold change > 1 and adj.p < 0.05). This study aimed to explore the role and underlying mechanisms of HERC5 in OSCC development.

Results: High HERC5 expression in OSCC tissues was confirmed by our hospital validation cohort and positively correlated with primary tumor stages. Subsequent functional studies demonstrated that knockdown of HERC5 inhibited the migratory and invasive capabilities with decrease of Vimentin and increase of E-cadherin in OSCC cells. In cisplatin treatment, cell survival rates were significantly reduced in HERC5-silencing OSCC cells, accompanied by the increase in cytotoxicity, DNA damage and apoptosis. OSCC cell-derived tumor xenograft displayed that HERC5 depletion inhibited pulmonary metastasis as well as restored the cisplatin-induced tumor burden. In line with this, overexpression of HERC5 yielded the opposite alterations both in vivo and in vitro. Mechanistically, UDP-glucose 6-dehydrogenase (UGDH) was identified as a HERC5-binding protein. Cysteine residue at position 994 in the HECT domain of HERC5 catalyzed the conjugation of ubiquitin-like protein Interferon-induced 15 kDa protein (ISG15) to UGDH (ISGylation of UGDH) and facilitated its phosphorylation, therefore enhancing SNAI1 mRNA stability. SNAI1 depletion inhibited HERC5 overexpression-triggered invasion and cisplatin resistance of OSCC cells.

Conclusions: Our study indicates that HERC5 may be a promising therapeutic target for OSCC.

E3连接酶herc5催化的UGDH异构化促进了snai1介导的口腔鳞状细胞癌的肿瘤转移和顺铂耐药。
背景:口腔鳞状细胞癌(OSCC)是世界范围内癌症相关死亡的主要原因之一,由于其高侵袭性和耐药性。先前的研究已经揭示了HECT和RLD结构域包含E3泛素蛋白连接酶5 (HERC5)在癌症中的重要作用。6个GEO基因微阵列鉴定出HERC5是OSCC组织或细胞中显著上调的基因(log2 Fold change > 1 and adj.p)结果:我院验证队列证实了HERC5在OSCC组织中的高表达,且与原发肿瘤分期呈正相关。随后的功能研究表明,敲低HERC5抑制了OSCC细胞的迁移和侵袭能力,并导致Vimentin减少,E-cadherin增加。在顺铂治疗中,herc5沉默的OSCC细胞的细胞存活率显著降低,并伴有细胞毒性、DNA损伤和凋亡的增加。OSCC细胞来源的肿瘤异种移植显示HERC5缺失抑制肺转移并恢复顺铂诱导的肿瘤负荷。与此一致,HERC5过表达在体内和体外均产生相反的改变。机制上,udp -葡萄糖6-脱氢酶(UGDH)被鉴定为herc5结合蛋白。HERC5 HECT结构域994位半胱氨酸残基催化泛素样蛋白干扰素诱导的15kda蛋白(ISG15)与UGDH结合(UGDH的isg酰化)并促进其磷酸化,从而增强SNAI1 mRNA的稳定性。SNAI1缺失抑制HERC5过表达引发的OSCC细胞侵袭和顺铂耐药。结论:我们的研究表明HERC5可能是一个有希望的OSCC治疗靶点。
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来源期刊
Biology Direct
Biology Direct 生物-生物学
CiteScore
6.40
自引率
10.90%
发文量
32
审稿时长
7 months
期刊介绍: Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.
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