Interplay between epigenetic alterations and piRNA expression in cancer development

PIWI-interacting RNAs (piRNAs) are small non-coding RNAs generated from longer precursor transcripts through primary processing and, in selected biological contexts, a secondary ping-pong amplification cycle. They associate with PIWI proteins to target and silence transposable elements (TEs), and dysregulation of the PIWI-piRNA pathway has been reported in multiple human cancers. In physiological germline models, epigenetic modifications - including DNA methylation, histone modifications, RNA modifications, and chromatin remodeling - coordinately regulate the activity of piRNA clusters to ensure proper piRNA biogenesis. However, in tumor cells, how epigenetic modifications influence piRNA transcription and processing remains poorly characterized, with most studies focusing on how dysregulated piRNAs drive tumorigenesis via epigenetic or epitranscriptomic mechanisms. This review also discusses species-specific differences, limitations in somatic piRNA annotation, and the evidence needed to distinguish association from mechanism. DNMT/HDAC inhibitors, dietary bioactive compounds, and deactivated Cas9 (dCas9)-based epigenome editing may provide useful experimental or therapeutic approaches, but piRNA-directed epigenetic therapy remains preclinical.