RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells.
RBM5-AS1 Is Critical for Self-Renewal of Colon Cancer Stem-like Cells.
复制标题
DOI：
10.1158/0008-5472.can-15-1824
复制
发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Walsh MJ
中科院分区：
文献类型：
--
作者：
Di Cecilia S;Zhang F;Sancho A;Li S;Aguiló F;Sun Y;Rengasamy M;Zhang W;Del Vecchio L;Salvatore F;Walsh MJ
肿瘤起始细胞(CIC)经历了不对称的生长模式，增加了表型多样性，驱动了化疗耐药和肿瘤复发的选择。WNT信号是结肠癌的一个标志，通常由APC突变引起，该突变使β-连环蛋白和myc激活。越来越多的证据表明，长的非编码RNA(LncRNA)有助于结肠癌细胞的干性特征。在本研究中，我们报告了在结肠CIC球体形成过程中lncRNA RBM5-AS1/LUST的丰富。它的沉默削弱了WNT信号，而它的过表达增强了WNT信号，细胞在无血清培养中的生长和存活。Rbm5-AS1以前很少被鉴定，我们确定它是一个核保留的转录本，选择性地与β-连环蛋白相互作用。机制研究表明，rBM5AS1的沉默或过表达分别导致与WNT靶基因SGK1、YAP1和MYC结合的TCF4复合体中β-连环蛋白的丢失或保留。我们的工作表明，RBM5-AS1活性对于结肠癌干细胞的功能启动至关重要。此外，它还通过与β-连环蛋白的物理相互作用，定义了rbm5-as1在WNT途径中的作用机制，帮助组织支持结肠CIC功能的转录复合体。
Cancer initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC. Accumulating evidence indicates that long non-coding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC. Its silencing impaired WNT signaling, whereas its overexpression enforced WNT signaling, cell growth and survival in serum-free media. RBM5-AS1 has been little characterized previously and we determined it to be a nuclear-retained transcript that selectively interacted with β-catenin. Mechanistic investigations showed that silencing or overexpression of RBM5-AS1 caused a respective loss or retention of β-catenin from TCF4 complexes bound to the WNT target genes SGK1, YAP1 and MYC. Our work suggests that RBM5-AS1 activity is critical for the functional enablement of colon cancer stem-like cells. Further, it defines the mechanism of action of RBM5-AS1 in the WNT pathway via physical interactions with β-catenin, helping organize transcriptional complexes that sustain colon CIC function.