Post-transcriptional repression of GSNOR by microRNAs regulates S-nitrosylation and fuels breast cancer progression

The denitrosylase S-nitrosoglutathione reductase (GSNOR) is a central regulator of nitric oxide (NO) signaling, by controlling protein S-nitrosylation. GSNOR is downregulated in several human cancers, with breast cancer representing one of the major hits. However, the mechanisms driving its suppression and its precise role in tumor progression remain elusive. Here, we identify microRNAs as key post-transcriptional regulators of GSNOR in breast cancer, specifically miR-455-3p and miR-519a-5p. Restoring GSNOR levels, either directly or by inhibiting these onco-miRs, reduced global protein S-nitrosylation, including that of glycogen synthase kinase 3β (GSK3β). This event was associated with decreased GSK3β inhibitory phosphorylation and consequent subsequent suppression of oncogenic signaling pathways. Functionally, GSNOR restoration inhibited epithelial-mesenchymal transition by increasing E-cadherin and reducing nuclear SNAI1 levels, attenuated β-catenin signaling, and impaired cell invasion, motility, and mammospheres viability. Altogether, our findings unveil a novel regulatory axis in which specific microRNAs control protein S-nitrosylation by targeting GSNOR, thereby driving breast cancer progression, and establish GSNOR as a crucial tumor suppressor.