LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma
LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma
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LNCAROD 通过 m6A 甲基化来稳定，并通过与头颈鳞状细胞癌中的 HSPA1A 和 YBX1 形成三元复合物来促进癌症进展
DOI：
10.1002/1878-0261.12676
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发表时间：
2020-04-13
影响因子：
6.6
通讯作者：
Xiang, Bo
中科院分区：
文献类型：
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作者：
Ban, Yuanyuan;Tan, Pingqing;Xiang, Bo
头颈部鳞状细胞癌(HNSCC)约占全球所有癌症的4%。在这项研究中，我们从癌症基因组图谱数据库中分析了502例HNSCC患者的长非编码RNA(LncRNA)的表达谱。在HNSCC和正常组织中差异表达的LncRNAs中，LNCAROD在HNSCC中高表达，并与晚期T分期和总生存期缩短有关。METTL3和METTL14介导的N6-甲基腺苷(M6A)修饰增强了LNCAROD在HNSCC细胞中的稳定性。LNCAROD的缺失降低了细胞的增殖、体外的迁移和体内的致瘤性，而过表达的LNCAROD则起到相反的作用。LNCAROD主要分布在细胞核内，与YBX1和HSPA1A蛋白结合。沉默YBX1或HSPA1A均不影响LNCAROD水平。然而，LNCAROD的缺失导致YBX1蛋白的半衰期缩短。从机制上讲，LNCAROD通过促进YBX1-HSPA1A蛋白-蛋白质之间的相互作用来保护YBX1免受蛋白酶体降解。LNCAROD过表达细胞中HSPA1A的缺失导致YBX1蛋白的蛋白酶体加速降解。此外，Flag-YBX1在LNCAROD沉默细胞中的重新表达挽救了HNSCC细胞的恶性行为。我们的研究表明，LNCAROD是一种致癌的LncRNA，M6A修饰的异常可能是HNSCC中LNCAROD异常表达的原因。LNCAROD作为YBX1和HSPA1A相互作用的支架，阻止YBX1在HNSCC细胞中的蛋白酶体降解。
Head and neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide. In this study, we analyzed the expression profile of the long noncoding RNA (lncRNA) of 502 HNSCC patients from The Cancer Genome Atlas database. Among the differentially expressed lncRNAs between HNSCC and normal samples, LNCAROD is overexpressed in HNSCC and associated with advanced T stage and shortened overall survival. The N6-methyladenosine (m6A) modification mediated by METTL3 and METTL14 enhanced the stability of LNCAROD in HNSCC cells. Depletion of LNCAROD attenuated cell proliferation, mobility in vitro, and tumorigenicity in vivo, whereas overexpression of LNCAROD exerted opposite effects. LNCAROD is mainly distributed in nucleus and binds with YBX1 and HSPA1A proteins. Silencing either YBX1 or HSPA1A did not affect the level of LNCAROD. However, loss of LNCAROD led to shortened half-life of YBX1 protein. Mechanistically, LNCAROD protected YBX1 from proteasomal degradation by facilitating YBX1-HSPA1A protein-protein interaction. Depletion of HSPA1A in LNCAROD-overexpressing cells resulted in accelerated proteasomal degradation of YBX1 protein. Moreover, re-expression of Flag-YBX1 in LNCAROD-silenced cells rescued malignant behavior of HNSCC cells. Our study indicates that LNCAROD is an oncogenic lncRNA and dysregulation of m6A modification might account for aberrant expression of LNCAROD in HNSCC. LNCAROD acts as a scaffold for the interaction between YBX1 and HSPA1A, preventing proteasomal degradation of YBX1 in HNSCC cells.