NRBF2 Regulates the Chemoresistance of Small Cell Lung Cancer by Interacting With the P62 Protein in the Autophagy Process

Abstract

SUMMARY Reversing chemotherapy resistance in small cell lung cancer (SCLC) is crucial to improve patient prognosis. It is important to elucidate the mechanisms of chemoresistance and determine therapeutic targets for SCLC. The present study aims to investigate the underlying mechanisms in SCLC chemoresistance. We screen that nuclear receptor binding factor 2 (NRBF2) is a poor prognostic factor in SCLC. A correlation was identified between high NRBF2 expression and poor overall survival in the clinical local-SCLC cohort. The effects of NRBF2 on chemoresistance were determined in SCLC using a patient-derived xenograft model. The effect and underlying molecular mechanisms of NRBF2 in the autophagy process in SCLC were examined. NRBF2 positively regulated autophagy, leading to drug resistance in SCLC. The microtubule interacting and transport (MIT) domain of NRBF2 directly interacted with the PB1 domain of P62, a core autophagy marker. This interaction increased autophagic P62 body formation, revealing the regulatory role of NRBF2 in autophagy. Notably, NRBF2 was directly modulated by the transcription factor XRCC6, likely explaining the differential NRBF2 expression in chemosensitive and chemoresistant SCLC. The MIT domain of NRBF2 interacts with the PB1 domain of P62 to regulate the autophagy process, resulting in SCLC chemoresistance. NRBF2 is likely a useful chemotherapy response marker and therapeutic target in SCLC.