期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 7, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-022-01033-8
关键词
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资金
- National Natural Science Foundation of China [81788101, 31870909, 31770937]
- CAMS Innovation Fund for Medical Sciences [2021-1-I2M-017]
- Shanghai Sailing Project [21YF1458000]
This study identifies ZCCHC4 as a potential therapeutic target and predictor of poor prognosis in multiple types of cancer. ZCCHC4 promotes chemoresistance and inhibits apoptosis in cancer cells through its interaction with AL133467.2. Furthermore, ZCCHC4 blocks the interaction between AL133467.2 and gamma H2AX, leading to increased chemoresistance. These findings provide mechanistic insights into the roles of RNA-binding proteins in cancer progression and treatment.
RNA-binding proteins (RBPs) play important roles in cancer development and treatment. However, the tumor-promoting RBPs and their partners, which may potentially serve as the cancer therapeutic targets, need to be further identified. Here, we report that zinc finger CCHC domain-containing protein 4 (ZCCHC4) is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma (HCC), pancreatic cancer and colon cancer. ZCCHC4 promotes chemoresistance of HCC cells to DNA-damage agent (DDA) both in vitro and in vivo. HCC cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDA-induced antitumor effect. Mechanistically, ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA (lncRNA) AL133467.2 to hamper its pro-apoptotic function. Also, ZCCHC4 blocks the interaction between AL133467.2 and gamma H2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and gamma H2AX interaction for enhancing chemosensitivity in HCC cells. Together, our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects, providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.
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