title: Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis.
abstract: BCL-X mRNA alternative splicing generates pro-apoptotic BCL-XS or anti-apoptotic BCL-XL gene products and the mechanism that regulates splice shifting is incompletely understood. We identified and characterized a long non-coding RNA (lncRNA) named INXS, transcribed from the opposite genomic strand of BCL-X, that was 5- to 9-fold less abundant in tumor cell lines from kidney, liver, breast and prostate and in kidney tumor tissues compared with non-tumors. INXS is an unspliced 1903 nt-long RNA, is transcribed by RNA polymerase II, 5'-capped, nuclear enriched and binds Sam68 splicing-modulator. Three apoptosis-inducing agents increased INXS lncRNA endogenous expression in the 786-O kidney tumor cell line, increased BCL-XS/BCL-XL mRNA ratio and activated caspases 3, 7 and 9. These effects were abrogated in the presence of INXS knockdown. Similarly, ectopic INXS overexpression caused a shift in splicing toward BCL-XS and activation of caspases, thus leading to apoptosis. BCL-XS protein accumulation was detected upon INXS overexpression. In a mouse xenograft model, intra-tumor injections of an INXS-expressing plasmid caused a marked reduction in tumor weight, and an increase in BCL-XS isoform, as determined in the excised tumors. We revealed an endogenous lncRNA that induces apoptosis, suggesting that INXS is a possible target to be explored in cancer therapies.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Carlos
authors.initials: C
authors.lastname: DeOcesano-Pereira
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Murilo S
authors.initials: MS
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Kleber S
authors.initials: KS
authors.lastname: Parreira
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Ayupe
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Jacysyn
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Gustavo P
authors.initials: GP
authors.lastname: Amarante-Mendes
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil Instituto Nacional de Ciência e Tecnologia em Oncogenômica, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Reis
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil Instituto Nacional de Ciência e Tecnologia em Oncogenômica, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil verjo@iq.usp.br.
authors.forename: Sergio
authors.initials: S
authors.lastname: Verjovski-Almeida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D012326:RNA Splicing; D062085:RNA, Long Noncoding / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D051020:bcl-X Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; D020033:Protein Isoforms; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D051020:bcl-X Protein; D020169:Caspases