Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
109
Journal Issue
52
Pages
E3659-E3667
Date Issued
2012
Author(s)
Li Q.
Shahamatdar S.
Hsu D.
Schetter A.J.
Swatkoski S.
Mannan P.
Garfield S.
Gucek M.
Kim M.K.H.
Annunziata C.M.
Creighton C.J.
Emanuele M.J.
Harris C.C.
Giaccone G.
Luo J.
Abstract
Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival.
SDGs
Other Subjects
centromere protein E; enhancer of rudimentary homolog protein; K ras protein; protein; small nuclear ribonucleoprotein; small nuclear ribonucleoprotein Sm D3; unclassified drug; article; cancer survival; cell survival; chromosome aberration; colorectal cancer; controlled study; cytotoxicity; gene expression profiling; gene mutation; human; human cell; mitosis; priority journal; protein analysis; protein function; protein protein interaction; RNA splicing; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Chromosomal Proteins, Non-Histone; Chromosomes, Human; Colorectal Neoplasms; Conserved Sequence; Evolution, Molecular; Gene Expression Regulation, Neoplastic; Humans; Mutation; Oncogenes; Protein Binding; Proto-Oncogene Proteins; ras Proteins; RNA Splicing; RNA, Messenger; snRNP Core Proteins; Survival Analysis; Transcription Factors
Type
journal article