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Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis

Carlos DeOcesano-Pereira¹, Murilo S Amaral¹, Kleber S Parreira¹

¹Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brasil.

Nucleic Acids Research

|July 5, 2014

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.

Insights

A newly discovered long non-coding RNA, INXS, promotes apoptosis by shifting BCL-X splicing toward the pro-apoptotic BCL-XS isoform. This finding suggests INXS as a potential therapeutic target for cancer treatment.

Area of Science:

Molecular Biology
Cancer Research
RNA Biology

Background:

Alternative splicing of BCL-X mRNA produces BCL-XS (pro-apoptotic) and BCL-XL (anti-apoptotic) isoforms.
The regulatory mechanisms controlling BCL-X alternative splicing remain incompletely understood.
Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in gene regulation and disease.

Purpose of the Study:

To identify and characterize novel regulatory factors involved in BCL-X alternative splicing.
To investigate the role of a newly identified lncRNA, INXS, in apoptosis and cancer.
To explore the therapeutic potential of INXS in cancer treatment.

Main Methods:

Identification and characterization of the INXS lncRNA.
Analysis of INXS expression levels in tumor cell lines and tissues.
Experimental manipulation of INXS expression (knockdown and overexpression) in cancer cells.
Assessment of BCL-X splicing, apoptosis markers (caspases), and protein levels.
In vivo studies using a mouse xenograft model.

Main Results:

INXS lncRNA expression was significantly reduced in various tumor types compared to non-tumor samples.
Increased INXS expression correlated with a shift in BCL-X splicing towards BCL-XS, caspase activation, and apoptosis.
INXS knockdown abrogated apoptosis-inducing agent-mediated effects.
Overexpression of INXS in vitro and in vivo led to BCL-XS accumulation and tumor growth inhibition.
INXS binds to the Sam68 splicing modulator.

Conclusions:

INXS is an endogenous lncRNA that regulates BCL-X alternative splicing to promote apoptosis.
Reduced INXS expression is associated with multiple cancer types.
INXS represents a promising novel therapeutic target for cancer treatment.

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