title: Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.
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.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Meng-Tzu
authors.initials: MT
authors.lastname: Weng
authors.forename: Jih-Hsiang
authors.initials: JH
authors.lastname: Lee
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.forename: Qiuning
authors.initials: Q
authors.lastname: Li
authors.forename: Sina
authors.initials: S
authors.lastname: Shahamatdar
authors.forename: Dennis
authors.initials: D
authors.lastname: Hsu
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.forename: Stephen
authors.initials: S
authors.lastname: Swatkoski
authors.forename: Poonam
authors.initials: P
authors.lastname: Mannan
authors.forename: Susan
authors.initials: S
authors.lastname: Garfield
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Marianne K H
authors.initials: MK
authors.lastname: Kim
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Emanuele
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.forename: Jin-Chuan
authors.initials: JC
authors.lastname: Sheu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D002877:Chromosomes, Human / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D017124:Conserved Sequence; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*; D055517:snRNP Core Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C484495:ERH protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C526412:SNRPD3 protein, human; D014157:Transcription Factors; C068688:centromere protein E; D055517:snRNP Core Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins