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NIT2 epigenetically restrains oxidative phosphorylation to overcome fluorouracil resistance in gastric cancer

GSE223789 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2025/12/31 Platform GPL18573
Summary
Fluorouracil (5-FU) chemoresistance is an important reason for the postoperative recurrence and poor prognosis of gastric cancer, but there is still no effective way to overcome chemoresistance. Here, by using the CRISPR/Cas9 system, we identify nitrilase family member 2 (NIT2) reverses chemoresistance, regardless of its metabolic function. NIT2 depletion causes H3K14 acetylation (H3K14ac) increase and NF-κB signalling activation, in turn upregulating oxidative phosphorylation (OXPHOS) and promoting chemoresistance. Mechanistically, NIT2 prevents BRD1 from binding histones and releases ING4 to degrade the transcription factor RELA. Upon 5-FU stimulation, the E3 ligase CCNB1IP1 interacts with NIT2 to cause autophagic degradation of NIT2. In addition, NIT2 downregulation correlates with poor prognosis in gastric cancer patients, and this is probably related to the promotion of OXPHOS. Our finding highlights the nonenzymatic function of NIT2 in chemoresistance and show that the blockade of OXPHOS by metformin can enhance chemosensitivity to 5-FU upon loss of NIT2.
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Direct links to NCBI, no account and no request form: the whole study as GSE223789_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 4 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA928383 and SRA study SRP419263. Searching any of these in the dataset finder brings you back here.

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