Identification and characterization of novel ETV4 splice variants in prostate cancer

ETV4, one of the ETS proteins overexpressed in prostate cancer, promotes migration, invasion and proliferation in prostate cells. This study has identified a series of previously unknown ETV4 alternatively spliced transcripts in human prostate cell lines. Their expression has been demonstrated with various unbiased techniques, including Nanopore sequencing. Most of these transcripts originate from an in-frame exon skipping and, thus, are expected to be translated into ETV4 protein isoforms. The functional analysis of the most abundant among these isoforms has showed that they still bear an activity, namely a reduced ability to promote proliferation and a retained/residual one to trigger transcriptional activation with variable efficacy towards different ETV4 target genes. Alternatively spliced genes are common in cancer cells: TCGA database analysis has documented the abundance of these novel ETV4 transcripts in prostate tumors, in contrast to peritumoral tissues. Since none of their translated isoforms have acquired a higher oncogenic potential, such abundance is likely to reflect the tumor deranged splicing machinery. However, it is also possible that their interaction with the canonical variants may contribute to the biology and the clinics of prostate cancer. Further investigations are needed to elucidate the biological role of these ETV4 transcripts and of their putative isoforms.