HFE145 MBNL1 knockdown cells were generated using a siRNA. Control cells are similarly transfected but with scrambled siRNA

Aberrant splicing is common in cancer. Here, we demonstrate that the down-regulation of the RNA binding protein MBNL1 promotes cancer stem cell-like (CSC-like) properties including tumor-initiation, self-renewal, migration and invasion by upregulating CSC-specific splice-isoforms. Particularly, the up-regulation of MAP2K7?exon2 isoform activates JNK which in turn leads to further up-regulation of MAP2K7?exon2 and down-regulation of MBNL1, thereby forming a feedback loop. This MBNL1-MAP2K7?exon2-JNK loop promotes CSC-like properties. Inhibition of JNK ameliorates stemness phenotypes driven by the MBNL1-MAP2K7?exon2-JNK loop. Remarkably, MBNL1 is down-regulated and MAP2K7?exon2 isoform is up-regulated in several cancer types. Down-regulation of MBNL1 is correlated with poor survival in gastric, lung and breast cancer. We propose MBNL1-low or MAP2K7?exon2-high as a biomarker for predicting sensitivity to treatment with JNK inhibitors.