Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKCα. The depletion of PHF8 or PKCα greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKCα expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKCα-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKCα, and PTEN showed a positive correlation between PHF8 and PKCα but negative correlations between PHF8 and PTEN and between PKCα and PTEN. Moreover, high PHF8-PKCα expression was significantly correlated with worse prognosis. Together, our results suggest that the PKCα-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.

需要针对晚期胃癌（GC）的靶向治疗，尤其是HER2阴性GC（占大多数病例）（80％至88％）。在这项研究中，对参与多种生物学过程和疾病的赖氨酸组蛋白脱甲基酶（KDM）进行了计算机分析，结果表明，PHD手指蛋白8（PHF8，KDM7B）与HER2阴性GC的不良临床结果显着相关。PHF8的耗竭显着降低了GC细胞和小鼠异种移植物中的癌症进展。基于微阵列分析，PHF8调控的基因参与细胞迁移/运动。值得注意的是，PHF8在PRKCA启动子上与c-Jun相互作用编码PKCα。PHF8或PKCα的耗竭极大地上调了PTEN表达，这可以通过异位表达PKCα表达载体或活性Src来挽救。这些提示PTEN去稳定化主要通过PKCα-Src轴发生。用Midostaurin或bosutinib处理的GC细胞在体外和斑马鱼模型中均能显着抑制迁移。对PHF8，PKCα和PTEN的免疫组织化学分析显示PHF8和PKCα之间呈正相关，而PHF8与PTEN之间以及PKCα和PTEN之间呈负相关。此外，PHF8-PKCα高表达与不良预后显着相关。总之，我们的结果表明，受PHF8 / c-Jun调节的PKCα-Src-PTEN途径是HER2阴性晚期GC的潜在预后/治疗靶标。