PICH activates Cyclin A1 transcription to drive S-phase progression and chemoresistance in gastric cancer.

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer (GC). However, fewer than half of GC patients benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein PICH as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted Cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes Cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative GC patients and prompting further investigation into the transcriptional activity of PICH.