NIT2 dampens BRD1 phase separation and restrains oxidative phosphorylation to enhance chemosensitivity in gastric cancer

作者：Ziyang Wang, Yuqin Di, Xiangqiong Wen, Ye Liu, Lvlan Ye, Xiang Zhang, Jiale Qin, Youpeng Wang, Huiying Chu, Guohui Li, Weijing Zhang, Xiongjun Wang, Weiling He · 发表于：Science Translational Medicine · 年份：2024 · DOI：10.1126/scitranslmed.ado8333 · 被引用次数：24 · 研究领域：Protein Degradation and Inhibitors、Epigenetics and DNA Methylation、Histone Deacetylase Inhibitors Research

5-Fluorouracil (5-FU) chemoresistance contributes to poor therapeutic response and prognosis of gastric cancer (GC), for which effective strategies to overcome chemoresistance are limited. Here, using a CRISPR-Cas9 system, we identified that nitrilase family member 2 (NIT2) reverses chemoresistance independent of its metabolic function. Depletion or low expression of NIT2 led to 5-FU resistance in GC cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, NIT2 interacted with bromodomain-containing protein 1 (BRD1) to inhibit HBO1-mediated acetylation of histone H3 at lysine-14 (H3K14ac) and RELA-targeted oxidative phosphorylation (OXPHOS) gene expression. Upon 5-FU stimulation, NIT2 phosphorylation by Src at Y49 promoted the dissociation of NIT2 from BRD1, followed by binding to E3 ligase CCNB1IP1, causing autophagic degradation of NIT2. Consequently, reduced NIT2 protein resulted in BRD1 forming phase separation and binding to histone H3, as well as increased RELA stability due to suppression of inhibitor of growth family member 4-mediated RELA ubiquitination. In addition, NIT2 expression negatively correlated with H3K14ac and OXPHOS and positively correlated with the chemotherapeutic responses and prognosis of patients with GC. Our findings reveal the moonlighting function of NIT2 in chemoresistance and underscore that OXPHOS blockade by metformin enhances 5-FU chemosensitivity upon NIT2 loss.