Epigenetic loss of the piwi/pirna machinery in human testicular tumorigenesis

Abstract

Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia. Herein we have studied the putative existence of epigenetic aberrations in the activity of PI WI proteins, an Argonaute family protein subclass, and the small regulatory PI WI-interacting RNAs (piRNAs) in testicular cancer, as the PI WI/piRNA pathway plays a critical role in male germline development. We have observed the existence of promoter CpG island hypermethylation-associated silencing of PI WIL1, PI WIL2, PI WIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines. Most importantly, these epigenetic lesions occur in a context of piRNA downregulation and loss of DNA methylation of the LINE-1 repetitive sequences, one of the target genomic loci where the PI WI/piRNA machinery acts as a caretaker in non-transformed cells. © 2014 Landes Bioscience.