FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma

Abstract

Impaired Fas-mediated apoptosis is associated with poor clinical outcomes and cancer chemoresistance. Soluble Fas receptor (sFas), produced by skipping of exon 6, inhibits apoptosis by sequestering Fas ligand. Serum sFas is associated with poor prognosis of non-Hodgkin's lymphomas. We found that the alternative splicing of Fas in lymphomas is tightly regulated by a lncRNA corresponding to an antisense transcript of Fas (FAS-AS1). Levels of FAS-AS1 correlate inversely with production of sFas and FAS-AS1 binding to the RBM5 inhibits RBM5-mediated exon 6 skipping. EZH2, often mutated or overexpressed in lymphomas, hyper-methylates the FAS-AS1 promoter and represses the FAS-AS1 expression. EZH2-mediated repression of FAS-AS1 promoter can be released by DZNeP or overcome by ectopic expression of FAS-AS1, both of which increase levels of FAS-AS1 and correspondingly decrease expression of sFas. Treatment with Bruton’s tyrosine kinase (BTK) inhibitor or EZH2 knockdown decreases the levels of EZH2, RBM5 and sFas thereby enhances Fas-mediated apoptosis. This is the first report showing functional regulation of Fas repression by its antisense RNA. Our results reveal new therapeutic targets in lymphomas and provide a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing.

Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs

“…32 Briefly, cells were harvested by centrifugation, washed with ice-cold phosphate-buffered saline and lysed with RIPA cell lysis buffer (Cell Signaling, Danvers, MA, USA). Protein concentration was determined by the Bradford assay (BioRad, Hercules, CA, USA) according to the manufacturer's protocol.…”

Noncoding RNAs in Cancer Immunology

“…Treatment with Bruton's tyrosine kinase inhibitor or EZH2 knockdown decreased the expression of EZH2, RBM5, and sFas, thereby enhancing Fas-mediated apoptosis. This study is the fi rst report showing a lncRNA regulates the function of Fas, which provides a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing [ 76 ].…”

Gene Expression Profiling in Non-Hodgkin Lymphomas

“…LncRNAs have been implicated in the prognosis of breast, lung, and liver cancers, but the exact role of these noncoding RNAs is yet to be defined. Preliminary data have been recently presented at national meetings and have shown exciting implications of lncRNAs in lymphomas such as MCL and Hodgkin lymphoma [114]. Coding RNA may on occasion affect the function of ncRNA by acting as a competitive inhibitor through multiple binding sites as the case of HMGA2 and the Let7 family of miRNAs [115].…”