TMEFF2 and CD95L derived shRNAs promote prostate cancer cell death by targeting the essential androgen receptor pathway

A novel mechanism, Death Induced by Survival gene Elimination (DISE), has recently been described as a potential cancer therapy. DISE kills cancer cells through an RNA interference (RNAi) mechanism. We show that expression of certain shRNAs developed to target TMEFF2 promotes prostate cancer (PCa) cell death similar to DISE, and independently of TMEFF2 targeting/expression. In PCa cells, these shRNAs downregulate the androgen receptor (AR) and AR coregulatory genes, an effect that correlates with the presence of short seed matches in their 3'UTRs and which results in global androgen signaling inhibition and cell death. We have termed this mechanism Androgen Network DISE (AN-DISE). shL3, an shRNA to CD95L known to promote DISE in non-PCa cells, promotes AN-DISE in PCa cells by targeting the AR-signaling pathway. Overall design: LNCaPcells expressing control shRNA (shScramble), shL3 shRNA (against CD95L) or three different shRNAs to TMEFF2, shTMEFF2-3, shTMEFF2-4 and shTMEFF2-9 were grown in complete RPMI. RNA was extracted 55 hours after transductions and the differences in the transcriptome for each of the shRNAs were evaluated with respect to the shScramble control.