Metastasis-associated protein 1 (MTA1) regulates the catecholamine production homeostasis via transcriptional repression of aromatic l-amino acid decarboxylase (Aadc) in the interstitial cells of Cajal of mouse prostate

Abstract

Based on the lately identified role for the interstitial cells of Cajal (ICCs) of mouse prostate in catecholamine production, as well as the well-established role for the master coregulator metastasis-associated protein 1 (MTA1) in inflammation, we probed into the functional link between aberrant MTA1 expression and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using both a MTA1−/− mouse model of experimental autoimmune prostatitis (EAP) and an in vitro chronic prostatitis model in cultured murine ICCs. EAP-induced MTA1 expression was enriched in ICCs of mouse prostate. EAP resulted in a higher increase in the pelvic pain response in MTA1−/− mice compared to WT mice. Consistently, the ICCs from MTA1−/− mice produced higher levels of catecholamines upon induction of in vitro chronic prostatitis. Mechanistically, MTA1 could directly suppress the transcription of Aadc, a rate-limiting enzyme during catecholamine synthesis, in a HDAC2-depdendent manner. Importantly, treatment with AADC inhibitor NSD-1015 significantly ameliorated EAP-elicited pain response and catecholamine overactivity in MTA1−/− mice. Taken together, our findings reveal an inherent regulatory role of the MTA1/AADC pathway in the maintenance of catecholamine production homeostasis in prostate ICCs, and also point to a potential use of HDAC inhibitors and/or AADC inhibitors to treat CP/CPPS.