KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer.
KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer.
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DOI：
10.1038/s41419-022-05200-1
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发表时间：
2022-09-02
影响因子：
9
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Yao, Hanhui;Ren, Delong;Wang, Yichun;Wu, Liang;Wu, Yang;Wang, Wei;Li, Qidong;Liu, Lianxin
结直肠癌（CRC）是全球癌症相关死亡的第二大主要原因。然而，为改善患者预后，CRC进展的分子机制仍有待进一步明确。在本研究中，我们发现钾离子通道四聚化结构域包含蛋白（KCTD）基因家族成员KCTD9在CRC组织中普遍表达下调，且KCTD9的表达与CRC临床分期呈负相关。生存分析表明，肿瘤中KCTD9表达水平低的患者预后较差。功能分析显示，在体外和体内模型中，KCTD9过表达均抑制CRC细胞增殖和转移，而KCTD9基因敲低则促进CRC细胞增殖和转移。通过过表达或敲低在CRC细胞中调控KCTD9水平，结果显示KCTD9的表达正向影响β - 连环蛋白的降解水平，进而抑制Wnt信号通路，并降低Wnt通路靶基因的表达。从机制上看，我们发现KCTD9与β - 连环蛋白介导的基因转录共激活因子ZNT9（锌转运体9）相关。在CRC细胞中过表达KCTD9或敲低ZNT9，会增加β - 连环蛋白的多聚泛素化和蛋白酶体降解。反过来，KCTD9与ZNT9的相互作用破坏了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降低以及Wnt信号通路受到抑制。总之，我们的研究结果表明，KCTD9作为一种抑癌基因，通过使Wnt/β - 连环蛋白通路失活来抑制CRC细胞的增殖和转移。此外，KCTD9在CRC中频繁下调，提示其可能成为CRC潜在的预后评估和治疗靶点。
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.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
64.5
作者：
Liu J;Lichtenberg T;Hoadley KA;Poisson LM;Lazar AJ;Cherniack AD;Kovatich AJ;Benz CC;Levine DA;Lee AV;Omberg L;Wolf DM;Shriver CD;Thorsson V;Cancer Genome Atlas Research Network;Hu H
通讯作者：
Hu H
影响因子：
11.4
作者：
Kitagawa, M;Hatakeyama, S;Nakayama, K
通讯作者：
Nakayama, K
影响因子：
3.3
作者：
Ji H;Ding X;Zhang W;Zheng Y;Du H;Zheng Y;Song H;Li M;Jiang Y;Xie J;Wu M;Jiao P;Wang Z;Wu H;Zhong Y
通讯作者：
Zhong Y
影响因子：
11.8
作者：
Huang, Ya-Lin;Niehrs, Christof
通讯作者：
Niehrs, Christof