Lu Wenbin, Tang Jianjun, Wang Yue, Gu Xiaoyan, Zhang Hua, Liu Yungang, Xiao Ying, Zhu Qi, Deng Jianzhong, Shen Ying, Jiang Anqi, Xu Yixin, Jin Jianhua, Hou Yongzhong, Liu Qian
Department of Oncology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, 213017, China.
Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, 213017, China.
Cell Death Dis. 2025 Jul 17;16(1):532. doi: 10.1038/s41419-025-07875-8.
NKD1 is a known suppressor of the Wnt/β-catenin pathway. However, our previous study revealed that NKD1 could promote the proliferation and migration of colon cancer cells, enhancing colon cancer progression via unknown mechanisms. In the present study, we found that peroxisome proliferator-activated receptor δ (PPARδ) is a transcription factor of the NKD1 gene. By analyzing the differential protein expression profiles between SW620 and SW620-nkd1 cells, we found that NKD1 dramatically increased MYC protein expression. Further study revealed that the MYC protein was degraded mainly through the autophagy pathway in colon cancer cells and that NKD1 restrained this process by suppressing the interaction between LC3B and MYC proteins. Interestingly, we found that NKD1 inhibited the autophagy signaling pathway. In-depth research revealed that NKD1 bound to the MYC protein through the EF-hand domain, facilitating the entry of the MYC protein into the nucleus and inhibiting cell apoptosis. Moreover, NKD1 activated the expression of MYC downstream target genes through MYC. Functionally, the PPARδ/NKD1/MYC signaling pathway increased colon cancer cells' proliferation, migration and angiogenesis capabilities. Therefore, NKD1 may serve as a specific biomarker for colon cancer and a potential new target for tumor treatment.
NKD1是已知的Wnt/β-连环蛋白信号通路的抑制因子。然而，我们之前的研究表明，NKD1可促进结肠癌细胞的增殖和迁移，通过未知机制增强结肠癌进展。在本研究中，我们发现过氧化物酶体增殖物激活受体δ（PPARδ）是NKD1基因的转录因子。通过分析SW620和SW620-nkd1细胞之间的差异蛋白质表达谱，我们发现NKD1显著增加MYC蛋白表达。进一步研究表明，MYC蛋白在结肠癌细胞中主要通过自噬途径降解，而NKD1通过抑制LC3B与MYC蛋白之间的相互作用来抑制这一过程。有趣的是，我们发现NKD1抑制自噬信号通路。深入研究表明，NKD1通过EF-手结构域与MYC蛋白结合，促进MYC蛋白进入细胞核并抑制细胞凋亡。此外，NKD1通过MYC激活MYC下游靶基因的表达。在功能上，PPARδ/NKD1/MYC信号通路增强了结肠癌细胞的增殖、迁移和血管生成能力。因此，NKD1可能作为结肠癌的特异性生物标志物和肿瘤治疗的潜在新靶点。
