Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis. Issue 13 (3rd July 2014)

• Record Type: Journal Article
• Authors: DeOcesano-Pereira, Carlos; Amaral, Murilo S.; Parreira, Kleber S.; Ayupe, Ana C.; Jacysyn, Jacqueline F.; Amarante-Mendes, Gustavo P.; Reis, Eduardo M.; Verjovski-Almeida, Sergio
• Is Part Of: Nucleic acids research. Volume 42:Issue 13(2014)
• Page Start: 8343
• Page End: 8355
• Publication Date: 2014-07-03
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gku561
• Languages: English
• ISSNs: 0305-1048

Abstract

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.