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 γH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to DDAs. Knockout of ZCCHC4 promotes AL133467.2 and γH2AX 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.

中文翻译：

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RNA结合蛋白ZCCHC4通过破坏DNA损伤诱导的细胞凋亡来促进人类癌症的化学抗性

RNA 结合蛋白 (RBP) 在癌症发展和治疗中发挥重要作用。然而，需要进一步确定可能作为癌症治疗靶点的促肿瘤 RBP 及其伙伴。在这里，我们报告含有锌指 CCHC 结构域的蛋白 4 (ZCCHC4) 在多种人类癌症组织中异常高表达，并且与肝细胞癌 (HCC)、胰腺癌和结肠癌患者的不良预后和化疗耐药有关。ZCCHC4 在体外和体内均促进 HCC 细胞对 DNA 损伤剂 (DDA) 的化学抗性。ZCCHC4的HCC细胞缺乏减少了体内肿瘤生长，并且ZCCHC4表达的瘤内干扰明显增强了DDA诱导的抗肿瘤作用。机械地，ZCCHC4 通过与新的长链非编码 RNA (lncRNA) AL133467.2 相互作用来抑制其促凋亡功能，从而抑制 DNA 损伤诱导的 HCC 细胞凋亡。此外，ZCCHC4 在 DDA 治疗后阻断 AL133467.2 和 γH2AX 之间的相互作用，以抑制凋亡信号并促进对 DDA 的化学抗性。ZCCHC4 的敲除促进 AL133467.2 和 γH2AX 相互作用以增强 HCC 细胞的化学敏感性。总之，我们的研究将 ZCCHC4 确定为癌症预后不良的新预测因子和改善化疗效果的潜在目标，为 RBP 及其伙伴在癌症进展和化疗耐药中的作用提供机制见解。2 和 γH2AX 在 DDA 治疗后抑制凋亡信号并促进对 DDA 的化学抗性。ZCCHC4 的敲除促进 AL133467.2 和 γH2AX 相互作用以增强 HCC 细胞的化学敏感性。总之，我们的研究将 ZCCHC4 确定为癌症预后不良的新预测因子和改善化疗效果的潜在目标，为 RBP 及其伙伴在癌症进展和化疗耐药中的作用提供机制见解。2 和 γH2AX 在 DDA 治疗后抑制凋亡信号并促进对 DDA 的化学抗性。ZCCHC4 的敲除促进 AL133467.2 和 γH2AX 相互作用以增强 HCC 细胞的化学敏感性。总之，我们的研究将 ZCCHC4 确定为癌症预后不良的新预测因子和改善化疗效果的潜在目标，为 RBP 及其伙伴在癌症进展和化疗耐药中的作用提供机制见解。