Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore;
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 165897 Singapore, Singapore.
Proc Natl Acad Sci U S A. 2020 Jul 14;117(28):16391-16400. doi: 10.1073/pnas.2002499117. Epub 2020 Jun 29.
Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that was down-regulated in several common cancers. Down-regulation of predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between -low cancers and embryonic stem cells including a exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing ∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition.
主要拼接调节因子 MBNL1 塑造了在发育过程中驱动细胞分化的大型转录组变化。在这里，我们证明 MBNL1 是肿瘤去分化的抑制剂。我们在癌症基因组图谱中对匹配的肿瘤/正常对进行了调查，发现 在几种常见癌症中下调。 在乳腺癌、肺癌和胃腺癌中， 下调预示着总体生存率较差，并增加了三阴性乳腺癌的复发和远处转移。 MBNL1 的下调导致体外和体内的肿瘤发生和干细胞/祖细胞样特性增加。 在 -低癌症和胚胎干细胞之间共享一组离散的选择性剪接事件 (ASE)，包括一个外显子 2 剪接变体，通过 JNK 激活导致增加干细胞/祖细胞样特性。 因此，JNK 抑制能够逆转 ∆exon2 驱动的 MBNL1-低癌细胞的肿瘤去分化。 我们的工作阐明了驱动肿瘤去分化的替代性剪接机制，并确定了预测 JNK 抑制增强易感性的生物标志物。
