XRN2-mediated regulation of tumor suppressor microRNAs is of critical pathophysiological significance in Humans

Abstract

MicroRNAs (miRNAs) are critical regulators of diverse developmental and physiological processes in animals, and their dysregulation has been linked to various disorders and diseases. Not only multiple regulatory mechanisms acting at different levels of human miRNA biogenesis determine miRNA abundance and function, but a few recently identified factors by facilitating miRNA turnover also make critical contributions. We demonstrate that the ribonuclease XRN2, whose worm ortholog had previously been shown to actively degrade let-7 family of miRNAs, can degrade the mature forms of certain let-7 family members in multiple human cancer cell lines, without affecting their precursors. The XRN2-mediated turnover of let-7 has patho-physiological significance as XRN2 depletion results in a reduction in the expression of a number of oncogenes, and diminishes the proliferative and metastatic potential of cancer cells. The clinical relevance of these observations is also verified in tumour transcriptomics data from public RNA-sequencing datasets, where we observe that higher XRN2 mRNA expression is inversely correlated with the levels of mature let-7 miRNAs and associated with poor survival in hepatocellular carcinoma, lung adenocarcinoma, and glioblastoma. We also demonstrate that miRNA turnover is a step-wise process, where a miRNA is released from the grasp of Argonaute before its degradation. This yet unidentified miRNA releasing factor is proteinaceous in nature and its activity is kinetically linked with XRN2-mediated turnover of miRNAs. Our analyses of the patient-derived transcriptomics data also show that XRN2, via its regulation of let-7, affects pathways related to cellular proliferation, development, and signalling in a consistent manner across epithelial and glial cell lineages. Collectively, our studies suggest an important role of XRN2 in regulating cancer physiology through degradation of the let-7 family of miRNAs.

Dauer quiescence as well as continuity of the life cycle after dauer-exit in Caenorhabditis elegans are dependent on the endoribonuclease activity of XRN-2

“…8 ). Most of the revelations on miRNA metabolism in worms have been proven to be conserved 109, 120 , and the recent finding that the human homologue of worm XRN-2 regulates mature miRNAs that are of pathophysiological significance in several human cancers further strengthened this notion 112 . Therefore, it does not require any stretch of imagination to postulate that hsXRN2 might be playing regulatory roles in similar/ identical pathways, as described in this study, which are operational in equivalent cellular states and beyond, and thus it might be of foremost importance to human physiology, both in health and disease.…”

“…This phenomenon has a strong connection with metabolic events that are critical for the homeostasis of several quiescent stem/ progenitor cells as well as cancer stem cells (CSCs) 2A). It is possible that hsXRN2 also performs a similar regulatory role, and indeed it has recently been implicated in miRNA turnover in humans as well 112 . Thus, hsXRN2 holds immense potential as a therapeutic target in modulating cellular fates, especially in post-injury/ degenerated tissues, which are dependent on metabolic processes linked to FAO.…”

“…2A ). It is possible that hsXRN2 also performs a similar regulatory role, and indeed it has recently been implicated in miRNA turnover in humans as well 112 . Thus, hsXRN2 holds immense potential as a therapeutic target in modulating cellular fates, especially in post-injury/ degenerated tissues, which are dependent on metabolic processes linked to FAO.…”