CHFR is a tumor suppressor that not only recognizes poly(ADP-ribosylation) (PARylation) signals at the sites of DNA damage but also is downregulated in many types of cancer. However, the underlying mechanism linking its role in PARylation-mediated DNA damage repair and tumor suppression is unclear. Here, we examined a panel of gastric cancer cell lines as well as primary tissue samples from gastric cancer patients, and found that CHFR expression was silenced by DNA hypermethylation in gastric cancer including 38.46% of primary gastric cancers. DNMT1 was associated with aberrant methylation of CHFR, and the expression of CHFR was restored by DNMT1 inhibitor 5-aza-2-deoxycytidine (5-aza-CdR) treatment. Moreover, we found that loss of CHFR abolished DNA damage repair and sensitized gastric tumor cells to PARP inhibitor treatment. Thus, our study reveals a potential therapeutic approach for treating gastric cancer with PARP inhibitor and lacking CHFR can serve as a biomarker for predicting the efficacy of PARP inhibitor on the gastric tumor treatment in future.

CHFR是一种肿瘤抑制因子，它不仅可以识别DNA损伤部位的聚（ADP-核糖基化）（PARylation）信号，而且在许多类型的癌症中均被下调。但是，尚不清楚其在PARylation介导的DNA损伤修复和肿瘤抑制中作用的潜在机制。在这里，我们检查了一组胃癌细胞系以及来自胃癌患者的原发组织样品，发现在包括38.46％的原发性胃癌在内的胃癌中，CHFR表达被DNA高甲基化所沉默。DNMT1与CHFR的异常甲基化有关，并且通过DNMT1抑制剂5-aza-2-deoxycytidine（5-aza-CdR）处理恢复了CHFR的表达。而且，我们发现CHFR的丧失消除了DNA损伤修复，并使胃肿瘤细胞对PARP抑制剂治疗敏感。因此，