KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3
KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3
复制标题
KIAA1429 通过 GATA3 的 N6-甲基腺苷依赖性转录后修饰促进肝癌进展
DOI：
10.1186/s12943-019-1106-z
复制
发表时间：
2019-12-19
期刊：
影响因子：
37.3
通讯作者：
Wu, Hong
中科院分区：
文献类型：
--
作者：
Lan, Tian;Li, Hui;Wu, Hong
n6 -甲基腺苷（m6A）修饰是真核RNA转录物中最丰富的内部甲基化，在RNA加工中起着关键作用。KIAA1429是已知m6A甲基转移酶复合体中最大的组分，在m6A甲基化中起着至关重要的作用。然而，其在肝细胞癌（HCC）中的功能和机制仍不明确。方法采用定量PCR、western blot和免疫组化检测KIAA1429在肝癌组织中的表达。体外和体内研究了KIAA1429对肝癌细胞恶性表型的影响。采用MeRIP-seq、RIP-seq和RNA-seq对KIAA1429的靶基因进行鉴定。结果skiaa1429在HCC组织中表达明显上调。KIAA1429的高表达与HCC患者预后不良相关。在体外和体内，沉默KIAA1429抑制细胞增殖和转移。GATA3被确定为kiaa1429介导的m6A修饰的直接下游靶点。KIAA1429诱导GATA3 pre-mRNA 3 ' UTR上的m6A甲基化，导致rna结合蛋白HuR的分离和GATA3 pre-mRNA的降解。引人注目的是，从GATA3基因的反义链转录而来的长链非编码RNA GATA3- as （lncRNA）在KIAA1429与GATA3前体mrna的优先相互作用中起着氨基酸作用元件的作用。因此，我们发现KIAA1429或GATA3- as驱动的肿瘤生长和转移是由GATA3介导的。结论本研究提出了一种基于m6A修饰的复杂KIAA1429-GATA3调控模型，为肝癌发生转移过程中表观转录组失调提供了新的思路。
BackgroundN6-methyladenosine (m6A) modification, the most abundant internal methylation of eukaryotic RNA transcripts, is critically implicated in RNA processing. As the largest known component in the m6A methyltransferase complex, KIAA1429 plays a vital role in m6A methylation. However, its function and mechanism in hepatocellular carcinoma (HCC) remain poorly defined.MethodsQuantitative PCR, western blot and immunohistochemistry were used to measure the expression of KIAA1429 in HCC. The effects of KIAA1429 on the malignant phenotypes of hepatoma cells were examined in vitroandin vivo. MeRIP-seq, RIP-seq and RNA-seq were performed to identify the target genes of KIAA1429.ResultsKIAA1429 was considerably upregulated in HCC tissues. High expression of KIAA1429 was associated with poor prognosis among HCC patients. Silencing KIAA1429 suppressed cell proliferation and metastasis in vitro and in vivo. GATA3 was identified as the direct downstream target of KIAA1429-mediated m6A modification. KIAA1429 induced m6A methylation on the 3′ UTR of GATA3 pre-mRNA, leading to the separation of the RNA-binding protein HuR and the degradation of GATA3 pre-mRNA. Strikingly, a long noncoding RNA (lncRNA) GATA3-AS, transcribed from the antisense strand of the GATA3 gene, functioned as acis-acting element for the preferential interaction of KIAA1429 with GATA3 pre-mRNA. Accordingly, we found that the tumor growth and metastasis driven by KIAA1429 or GATA3-AS were mediated by GATA3.ConclusionOur study proposed a complex KIAA1429-GATA3 regulatory model based on m6A modification and provided insights into the epi-transcriptomic dysregulation in hepatocarcinogenesis and metastasis.