P4HA2 promotes the progression of papillary thyroid cancer by enhancing degradation of IκBα to activate NF-κB signaling pathway.

Abstract

Papillary thyroid cancer (PTC) is the most common malignancy of the endocrine system. Collagen prolyl 4-hydroxylase alpha subunit 2 (P4HA2) is a key enzyme involved in collagen metabolism. However, the expression and function of P4HA2 in PTC progression have not been well studied. Our previous proteomic data showed that the differential proteins in human PTC were significantly enriched in metabolic signaling pathways, with P4HA2 being the most up-regulated protein. Here, we found that P4HA2 promotes the proliferation and migration of PTC. The expression of P4HA2 is elevated and its elevation is associated with poor prognosis in human PTC specimens. Functionally, P4HA2 promotes the proliferative and migratory abilities of BHP10-3 and TPC-1 cells. Further studies showed that overexpression of P4HA2 significantly activates the NF-κB signaling pathway. Mechanistically, P4HA2 promotes the ubiquitination and degradation of inhibitor kappa B-alpha (IκBα) by directly binding, leading to activation of NF-κB signaling pathway. Furthermore, BAY 11-7082, an inhibitor of the NF-κB signalling pathway, reversed the promotion of PTC proliferation and metastasis by P4HA2 both in vivo and in vitro. In conclusion, P4HA2 activates the NF-κB signaling pathway by promoting proteasome-dependent degradation of IκBα, which in turn contributes to the proliferation and migration of PTC. Therefore, P4HA2 could be used as a potential therapeutic target for the treatment of PTC patients.