期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 28, 页码 16391-16400出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002499117
关键词
MBNL1; MAP2K7; JNK inhibitors; alternative splicing; tumor cell dedifferentiation
资金
- National Medical Research Council, Singapore [NMRC/OFYIRG/0065/2017, NMRC/CBRG/0104/2016]
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 MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 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 in-creased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between MBNL1-low cancers and embryonic stem cells including a MAP2K7 Delta exon2 splice variant that leads to increased stem/progen-itor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7 Delta 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.
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