The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53.
The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53.
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非编码RNA SNORD50A和SNORD50B介导的TRIM21-GMPS相互作用通过降解p53促进p53野生型乳腺癌的生长
DOI：
10.1038/s41418-021-00762-7
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发表时间：
2021-08
影响因子：
12.4
通讯作者：
Hou P
中科院分区：
文献类型：
--
作者：
Su X;Feng C;Wang S;Shi L;Gu Q;Zhang H;Lan X;Zhao Y;Qiang W;Ji M;Hou P
据报道，小核仁RNA SNORD 50 A和SNORD 50 B（SNORD 50 A/B）在不同类型的癌症中反复缺失，并通过结合并抑制KRAS癌蛋白的活性而作为推定的肿瘤抑制因子发挥作用。其缺失与较差的患者存活率相关。然而，在这项研究中，我们惊奇地发现SNORD 50 A/B缺失预测携带野生型p53的乳腺癌患者的生存率更高。功能研究表明，SNORD 50 A/B缺失可显著抑制p53野生型乳腺癌细胞的增殖、迁移、侵袭和致瘤能力，诱导细胞周期阻滞和凋亡，而对p53突变型乳腺癌细胞则具有相反的作用。这也得到了在p53野生型和突变的乳腺癌细胞中异位表达SNORD 50 A/B的支持。在机制上，SNORD 50 A/B通过在E3泛素连接酶TRIM 21和其底物GMPS之间形成复合物而明显增强它们之间的相互作用，从而促进GMPS泛素化及其随后的细胞质螯合。在p53野生型乳腺癌细胞中SNORD 50 A/B缺失将释放GMPS并诱导GMPS易位到细胞核中，在那里GMPS可以募集USP 7并与p53形成复合物，从而减少p53泛素化，稳定p53蛋白，并抑制癌细胞的恶性表型。总之，本研究首次报道了SNORD 50 A/B通过介导TRIM 21-GMPS相互作用在p53野生型乳腺癌中发挥致癌作用。
Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.
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影响因子：
21.3
作者：
Epping, Mirjam T.;Meijer, Lars A. T.;Bernards, Rene
通讯作者：
Bernards, Rene
影响因子：
5.9
作者：
Dong, Xue-Yuan;Guo, Peng;Boyd, Jeff;Sun, Xiaodong;Li, Qunna;Zhou, Wei;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
3.5
作者：
Dong, Xue-Yuan;Rodriguez, Carmen;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
16
作者：
Faesen, Alex C.;Dirac, Annette M. G.;Sixma, Titia K.
通讯作者：
Sixma, Titia K.
影响因子：
3.8
作者：
Heng, Yujing J.;Hankinson, Susan E.;Kraft, Peter
通讯作者：
Kraft, Peter