Chemoresistance is a primary factor limiting nasopharyngeal carcinoma (NPC) treatment. Growing evidence indicates that E3 ubiquitin ligases play a pivotal role in chemoresistance. Here, we identified that the E3 ubiquitin ligase RNF138 is significantly upregulated in NPC patients who do not respond to chemotherapy. Our study reveals that RNF138 promotes the K48-linked ubiquitination of hnRNPA0 at K133, thereby destabilizing WWOX mRNA. The subsequent loss of WWOX protein relieves the inhibition of JAK2 self-phosphorylation, leading to constitutive pathway activation. Consequently, RNF138-JAK2/STAT3 activation suppresses chemotherapy-induced apoptosis via reduced ROS production and promotes immune evasion by upregulating PD-L1. Clinically, high RNF138 expression correlated with poor prognosis and resistance to chemotherapy. In conclusion, this study unveils the RNF138-hnRNPA0-WWOX axis as a driver of JAK2/STAT3 activation, leading to both chemoresistance and immune evasion in NPC. This work positions RNF138 as a valuable biomarker to guide individualized chemotherapy, and highlights JAK inhibitors as a potential targeted therapy for NPC patients.
He et al. (Mon,) studied this question.