Ning Jiong, Sun Qi, Su Zijie, Tan Lifeng, Tang Yun, Sayed Sapna, Li Huan, Xue Vivian Weiwen, Liu Shanshan, Chen Xianxiong, Lu Desheng
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, China.
Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, China.
Front Oncol. 2022 Apr 12;12:844477. doi: 10.3389/fonc.2022.844477. eCollection 2022.
Casein kinase 1δ/ϵ (CK1δ/ϵ) are well-established positive modulators of the Wnt/β-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of β-catenin transcriptional activity by CK1δ/ϵ remain unclear. In this study, we found that CK1δ/ϵ could enhance β-catenin-mediated transcription through regulating β-catenin acetylation. CK1δ/ϵ interacted with Tip60 and facilitated the recruitment of Tip60 to β-catenin complex, resulting in increasing β-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1δ/ϵ or/and β-catenin. Furthermore, a CK1δ/CK1ϵ/β-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1δ and CK1ϵ significantly attenuated the interaction between β-catenin and Tip60. Notably, inhibition of CK1δ/ϵ or Tip60, with shRNA or small molecular inhibitors downregulated the level of β-catenin acetylation at K49 in colon cancer cells. Finally, combined treatment with CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had more potent inhibitory effect on β-catenin acetylation, the transcription of Wnt target genes and the viability and proliferation in colon cancer cells. Taken together, our results revealed that the transcriptional activity of β-catenin could be modulated by the CK1δ/ϵ-β-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.
酪蛋白激酶1δ/ε（CK1δ/ε）是Wnt/β-连环蛋白信号通路中公认的正向调节因子。然而，CK1δ/ε调节β-连环蛋白转录活性的分子机制仍不清楚。在本研究中，我们发现CK1δ/ε可通过调节β-连环蛋白的乙酰化来增强β-连环蛋白介导的转录。CK1δ/ε与Tip60相互作用，并促进Tip60募集到β-连环蛋白复合物中，导致β-连环蛋白第49位赖氨酸残基的乙酰化增加。重要的是，Tip60显著增强了由CK1δ/ε或/和β-连环蛋白诱导的SuperTopFlash报告基因活性。此外，在结肠癌细胞中检测到了CK1δ/CK1ε/β-连环蛋白/Tip60复合物。同时敲低CK1δ和CK1ε可显著减弱β-连环蛋白与Tip60之间的相互作用。值得注意的是，用短发夹RNA（shRNA）或小分子抑制剂抑制CK1δ/ε或Tip60可下调结肠癌细胞中β-连环蛋白第49位赖氨酸残基的乙酰化水平。最后，联合使用CK1抑制剂SR3029和Tip60抑制剂MG149对β-连环蛋白乙酰化、Wnt靶基因转录以及结肠癌细胞的活力和增殖具有更强的抑制作用。综上所述，我们的结果表明β-连环蛋白的转录活性可由CK1δ/ε-β-连环蛋白-Tip60轴调节，这可能是结肠癌的一个潜在治疗靶点。
