NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma.

Abstract

Nucleosome assembly protein 1-like 1 (NAP1L1) has been implicated in promoting tumor cell proliferation. However, its role in regulating autophagy in tumors, including nasopharyngeal carcinoma (NPC), remains unclear. In this study, we observed that autophagy-inducing agents reduced NAP1L1 protein levels without affecting its mRNA expression. Reduced NAP1L1 enhanced autophagosome formation and maturation, thereby promoting cisplatin (DDP) chemosensitivity in both in vitro and in vivo NPC models. Mechanistically, reduced NAP1L1 impaired the recruitment of ubiquitin-specific protease 14 (USP14), limiting the deubiquitination of heparin-binding growth factor (HDGF) and decreasing HDGF protein levels. In turn, reduced HDGF suppressed USP14-mediated p62 deubiquitination, leading to further declines in p62 protein levels. Notably, the F-box and WD repeat domain-containing protein 7 (FBXW7), an inhibitory E3 ubiquitin ligase, directly interacted with and ubiquitinated NAP1L1, promoting its degradation. This degradation triggered NPC autophagy and enhanced DDP chemosensitivity by disrupting NAP1L1-induced HDGF/p62 signaling. Clinically, NAP1L1 protein expression was inversely correlated with FBXW7 levels in NPC tissue samples. Patients exhibiting high NAP1L1 and low FBXW7 levels had the poorest DDP chemosensitivity and survival outcomes. Our findings demonstrate that FBXW7-mediated NAP1L1 degradation suppresses HDGF-p62 signaling, thereby inducing autophagy and enhancing DDP chemosensitivity. These results underscore the potential of NAP1L1 and FBXW7 as therapeutic targets for NPC treatment.