Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (52), p.E3659-E3667
• Main Authors: Weng, Meng-Tzu, Lee, Jih-Hsiang, Wei, Shu-Chen, Li, Qiuning, Shahamatdar, Sina, Hsu, Dennis, Schetter, Aaron J, Swatkoski, Stephen, Mannan, Poonam, Garfield, Susan, Gucek, Marjan, Kim, Marianne K H, Annunziata, Christina M, Creighton, Chad J, Emanuele, Michael J, Harris, Curtis C, Sheu, Jin-Chuan, Giaccone, Giuseppe, Luo, Ji
• Format: Article
• Language: English
• Subjects: Biochemistry; Biological Sciences; Cell Cycle - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - genetics; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes, Human - metabolism; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Conserved Sequence; Evolution, Molecular; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Mutation; Mutation - genetics; Oncogenes; PNAS Plus; Protein Binding; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; RNA Splicing - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-protein interactions; snRNP Core Proteins - metabolism; Survival Analysis; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1207673110

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.