Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Cell Death Dis. 2022 Sep 2;13(9):761. doi: 10.1038/s41419-022-05200-1.
Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of β-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of β-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of β-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between β-catenin and ZNT9, thereby leading to decreased β-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/β-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.
结直肠癌（CRC）是全球癌症死亡的第二大主要原因。然而，为了改善患者的预后，仍需要进一步明确 CRC 进展的分子机制。在这项研究中，我们发现 KCTD9，钾通道四聚化结构域包含（KCTD）基因家族的成员，在 CRC 组织中普遍下调，并且 KCTD9 表达与临床 CRC 分期呈负相关。生存分析表明，肿瘤表达低水平 KCTD9 的患者预后较差。功能分析表明，KCTD9 过表达抑制 CRC 细胞增殖和转移，而 KCTD9 敲低则促进了体外和体内模型中 CRC 细胞的增殖和转移。通过过表达或敲低 CRC 细胞中的 KCTD9 水平，发现 KCTD9 表达可正向影响 β-连环蛋白水平的降解，从而抑制 Wnt 信号通路并降低 Wnt 通路靶基因的表达。从机制上讲，我们发现 KCTD9 与 ZNT9（锌转运蛋白 9）相关，ZNT9 是 β-连环蛋白介导的基因转录的共激活因子。CRC 细胞中 KCTD9 的过表达或 ZNT9 的敲低增加了 β-连环蛋白的多泛素化和蛋白酶体降解。反过来，KCTD9-ZNT9 相互作用破坏了 β-连环蛋白与 ZNT9 之间的相互作用，从而导致 β-连环蛋白靶基因表达减少和 Wnt 信号通路抑制。总之，我们的研究结果表明，KCTD9 作为一种肿瘤抑制因子，通过失活 Wnt/β-连环蛋白通路来抑制 CRC 细胞的增殖和转移。此外，KCTD9 在 CRC 中经常下调提示 KCTD9 可能是 CRC 的一个潜在预后和治疗靶点。
