WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer.
WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer.
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WDHD1 对于 PTEN 失活三阴性乳腺癌的生存至关重要
DOI：
10.1038/s41419-020-03210-5
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发表时间：
2020-11-21
影响因子：
9
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Ertay A;Liu H;Liu D;Peng P;Hill C;Xiong H;Hancock D;Yuan X;Przewloka MR;Coldwell M;Howell M;Skipp P;Ewing RM;Downward J;Wang Y
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌类型，缺乏雌激素受体，孕酮受体和人表皮生长因子受体2，使其难以靶向治疗。靶向合成致死性是癌症治疗的另一种方法。TNBC显示磷酸酶和张力蛋白同源物（PTEN）表达的频繁丧失，这与不良预后和治疗反应相关。为了鉴定PTEN合成致死相互作用，在同基因PTEN阴性和阳性细胞中进行TCGA分析与全基因组siRNA筛选。在PTEN失活TNBC细胞存活所必需的候选基因中，WDHD1（WD重复序列和高迁移率族蛋白DNA结合蛋白1）表达在低与高PTENTNBC样品中增加。它也是siRNA筛选中的最高命中，并且其敲低显著抑制了PTEN阴性细胞中的细胞活力，这在2D和3D培养物中得到了进一步验证。从机制上讲，WDHD1对于介导PTEN失活的TNBC中蛋白质翻译的高需求是重要的。最后，在从TCGA获得的患者样品和具有临床病理信息的组织微阵列中证实了WDHD1在TNBC中的重要性。综上所述，WDHD1作为PTEN失活的TNBC细胞存活的必需基因，可能是TNBC的潜在生物标志物或治疗靶点。
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, making it difficult to target therapeutically. Targeting synthetic lethality is an alternative approach for cancer treatment. TNBC shows frequent loss of phosphatase and tensin homologue (PTEN) expression, which is associated with poor prognosis and treatment response. To identify PTEN synthetic lethal interactions, TCGA analysis coupled with a whole-genome siRNA screen in isogenic PTEN-negative and -positive cells were performed. Among the candidate genes essential for the survival of PTEN-inactive TNBC cells,WDHD1(WD repeat and high-mobility group box DNA-binding protein 1) expression was increased in the low vs. highPTENTNBC samples. It was also the top hit in the siRNA screen and its knockdown significantly inhibited cell viability in PTEN-negative cells, which was further validated in 2D and 3D cultures. Mechanistically, WDHD1 is important to mediate a high demand of protein translation in PTEN-inactive TNBC. Finally, the importance of WDHD1 in TNBC was confirmed in patient samples obtained from the TCGA and tissue microarrays with clinic-pathological information. Taken together, as an essential gene for the survival of PTEN-inactive TNBC cells,WDHD1could be a potential biomarker or a therapeutic target for TNBC.
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影响因子：
12.3
作者：
Boutros M;Brás LP;Huber W
通讯作者：
Huber W
人类复制体中关键接头蛋白AND-1的结构和聚合酶识别机制
影响因子：
4.8
作者：
Guan, Chengcheng;Li, Jun;Liang, Huanhuan
通讯作者：
Liang, Huanhuan
WDHD1 通过促进肺腺癌中 MAPRE2 泛素化导致顺铂耐药
影响因子：
4.7
作者：
Gong, Lian;Xiao, Mengqing;Cao, Ke
通讯作者：
Cao, Ke
DOI：
10.20517/cdr.2019.87
发表时间：
2019
期刊：
CANCER DRUG RESISTANCE
影响因子：
--
作者：
Bhaoighill, Muireann Ni;Dunlop, Elaine A.
通讯作者：
Dunlop, Elaine A.
影响因子：
4.8
作者：
Bermudez, Vladimir P.;Farina, Andrea;Hurwitz, Jerard
通讯作者：
Hurwitz, Jerard