NKD1 enhances colon cancer progression by inhibiting the autophagic degradation of MYC.

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.