ABSTRACT
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.
Footnotes
↵π Co-first Authors.
ABBREVIATIONS
- 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
