Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 28, Pages 16391-16400Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002499117
Keywords
MBNL1; MAP2K7; JNK inhibitors; alternative splicing; tumor cell dedifferentiation
Categories
Funding
- National Medical Research Council, Singapore [NMRC/OFYIRG/0065/2017, NMRC/CBRG/0104/2016]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available