Activation of ERK by altered RNA splicing in cancer

Many cancers carry change-of-function mutations affecting RNA splicing factors, however, less is known about the functional consequences of upregulated RNA splicing factors in cancer. Here, we demonstrate that SMNDC1, a poorly studied splicing factor, which we found to be upregulated in multiple carcinomas and associated with poor patient prognosis, promotes cell proliferation, clonal expansion, and tumor growth by promoting the retention of G-rich exons, which otherwise would be excluded or retained at a lower rate after RNA splicing in normal cells. Inclusion of exon 4 (E4) of MAPK3 (ERK1), which encodes both kinase phosphorylation sites (Thr202/Tyr204), was among the promoted exons by SMNDC1. Forced exclusion of MAPK3- E4 using anti-sense oligos inhibited the ERK1 phosphorylation, expression of target genes and decreased tumor cell growth. These data support that cancer cells exploit a “splicing switch” to promote ERK kinase activity and offer a druggable alternative to block oncogenic signaling and altered RNA splicing in cancer cells SIGNIFICANCE ERK signaling promotes tumor growth and survival. Exon 4 of MAPK3 (ERK1) encodes the activation phosphorylation sites of ERK1 kinase. Aberrant RNA splicing induced by SMNDC1 in cancer cells increases the retention of exon 4 during mRNA splicing, unleashes the kinase activity. SMNDC1 potentializes as a cancer therapeutic target. ### Competing Interest Statement The authors have declared no competing interest. * A3 : alternative 3’ splice site A5 : alternative 5’ splice site AF : alternative first exon AL : alternative last exon AS : alternative splicing BLCA : Bladder Urothelial Carcinoma BRCA : Breast Invasive Carcinoma CESC : Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma COAD : Colon Adenocarcinoma EOC : epithelial ovarian cancer ERK1 : Extracellular Signal-Regulated Kinase 1 ESCA : Esophageal Carcinoma GBM : Glioblastoma multiforme GNP : gold nanoparticles HGSOC : High Grade Serous Ovarian Cancer HNSC : Head and Neck Squamous Cell Carcinoma KIRC : Kidney Renal Clear Cell Carcinoma KIRP : Kidney Renal Papillary Cell Carcinoma LGG : Brain Lower Grade Glioma LIHC : Liver Hepatocellular Carcinoma LUAD : Lung Adenocarcinoma LUSC : Lung Squamous Cell Carcinoma MAPK3 : Mitogen Activated Protein Kinase 3 MX : mutually exclusive exons NAT : normal adjacent tissue OVCa : Ovarian cancer PAAD : Pancreatic Adenocarcinoma PCPG : Pheochromocytoma and Paraganglioma PDAC : pancreatic ductal adenocarcinoma PRAD : Prostate Adenocarcinoma RI : retained intron SE : skipping exon SARC : Sarcoma SKCM : Skin Cutaneous Melanoma SMNDC1 : survival motor neuron domain containing 1 snRNP : small nuclear ribonucleoprotein STAD : Stomach Adenocarcinoma TMA : tissue microarray TGCT : Testicular Germ Cell Tumors THYM : Thymoma THCA : Thyroid Carcinoma TUNEL : terminal deoxynucleotidyl transferase dUTP nick end labeling UCEC : Uterine Corpus Endometrial Carcinoma