title: Non-coding RNAs derived from an alternatively spliced REST transcript (REST-003) regulate breast cancer invasiveness.
abstract: RE1-Silencing Transcription factor (REST) has a well-established role in regulating transcription of genes important for neuronal development. Its role in cancer, though significant, is less well understood. We show that REST downregulation in weakly invasive MCF-7 breast cancer cells converts them to a more invasive phenotype, while REST overexpression in highly invasive MDA-MB-231 cells suppresses invasiveness. Surprisingly, the mechanism responsible for these phenotypic changes does not depend directly on the transcriptional function of REST protein. Instead, it is driven by previously unstudied mid-size (30-200 nt) non-coding RNAs (ncRNAs) derived from the first exon of an alternatively spliced REST transcript: REST-003. We show that processing of REST-003 into ncRNAs is controlled by an uncharacterized serine/arginine repeat-related protein, SRRM3. SRRM3 expression may be under REST-mediated transcriptional control, as it increases following REST downregulation. The SRRM3-dependent regulation of REST-003 processing into ncRNAs has many similarities to recently described promoter-associated small RNA-like processes. Targeting ncRNAs that control invasiveness could lead to new therapeutic approaches to limit breast cancer metastasis.
authors.affiliation: 1] Physiology &Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles [2] Dept of Biomedical Engineering, University of Southern California, Los Angeles.
authors.forename: Nan Sook
authors.initials: NS
authors.lastname: Lee
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgrafov
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: Tade
authors.initials: T
authors.lastname: Souaiaia
authors.affiliation: Physiology &Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles.
authors.forename: Adrineh
authors.initials: A
authors.lastname: Bonyad
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herstein
authors.affiliation: Neuroscience Graduate Program, University of Southern California, Los Angeles.
authors.forename: Joo Yeun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: Jihong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Dept of Medicine, Norris Cancer Center, University of Southern California, Los Angeles.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Pasadena City College, Pasadena.
authors.forename: Marcos
authors.initials: M
authors.lastname: Sixto
authors.affiliation: Dept of Ophthalmology, University of Southern California, Los Angeles, CA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Weitz
authors.affiliation: Dept of Medicine, Norris Cancer Center, University of Southern California, Los Angeles.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Psychiatry &the Behavioral Sciences, University of Southern California, Los Angeles.
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.affiliation: Dept of Pathology, Norris Cancer Center, University of Southern California, Los Angeles.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.affiliation: Department of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, CA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Salvaterra
authors.affiliation: Dept of Biomedical Engineering, University of Southern California, Los Angeles.
authors.forename: K Kirk
authors.initials: KK
authors.lastname: Shung
authors.affiliation: Physiology &Biophysics and Zilkha Neurogenetic Institute, University of Southern California, Los Angeles.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Chow
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D011506:Proteins; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C000608776:SRRM3 protein, human