A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

A divergent member of the polo-like kinase family, PLK4 is known for its canonical role in centriole duplication. Its non-canonical function and regulators are poorly defined. Here we investigated PLK4s activation and expression and regulations thereof in rat adventitial fibroblast cell-type transition induced by platelet-derived growth factor (PDGF-AA).\n\nExperiments using siRNA and selective inhibitor (centrinone-B) revealed a role for PLK4 not only in AA-induced proliferation/migration, but also in serum response factor (SRF) activation and smooth muscle -actin expression. PDGFR (receptor) inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and expression; P38 inhibition (siRNA, inhibitor) downstream of PDGFR also mitigated PLK4 activation. Furthermore, transcription of PLK4 (and PDGFR) was repressed by pan-inhibition of the bromodomain/extraterminal family of chromatin-bookmark readers (BRD2, BRD3, BRD4), an effect determined herein as mainly mediated by BRD4. In vivo, periadventitial administration of centrinone-B reduced collagen content and thickness of the adventitia in a rat model of carotid artery injury.\n\nIn summary, we have identified a non-canonical role for PLK4 in SRF activation and its regulations by BRD4/PDGFR-dominated pathways. Results in this study suggest PLK4 inhibition as a potential anti-fibrotic intervention.