Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, P.R. China.
Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, P.R. China.
Cancer Res. 2023 Nov 15;83(22):3767-3782. doi: 10.1158/0008-5472.CAN-23-1331.
The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (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 patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH.
PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.
化疗药物 5-氟尿嘧啶（5-FU）仍然是胃癌术后辅助治疗的基础。然而，由于化疗耐药性和有限的临床生物标志物，只有不到一半的胃癌患者受益于基于 5-FU 的化疗。在这里，我们确定 SNF2 蛋白 Polo 样激酶 1 相互作用的检查点解旋酶（PICH）作为 5-FU 化疗敏感性的预测因子，并描述了 PICH 不同于其在染色体分离中的作用的转录功能。PICH 以 ATP 酶依赖的方式与 RNA 聚合酶 II（Pol II）和 ATF4 在 CCNA1 启动子上形成转录复合物。PICH 复合物的结合促进了细胞周期蛋白 A1 的转录并加速了 S 期进程。过表达的 PICH 会损害人类类器官和患者来源的异种移植物中的 5-FU 化疗敏感性。此外，在接受 5-FU 化疗的术后患者中，升高的 PICH 表达与生存呈负相关。总之，这些发现揭示了 PICH 的一种 ATP 酶依赖的转录功能，该功能促进细胞周期蛋白 A1 的转录，从而导致 5-FU 化疗耐药性，为接受胃癌术后的患者提供了 5-FU 化疗敏感性的潜在预测生物标志物，并促使进一步研究 PICH 的转录活性。
PICH 以 ATP 酶依赖的方式与 Pol II 和 ATF4 结合形成转录复合物，促进细胞周期蛋白 A1 的表达，加速 S 期进程，并损害胃癌中的 5-FU 化疗敏感性。
