C-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer.

Abstract

Simple SummaryColorectal cancer (CRC) is the most common gastrointestinal tract malignancy. Previous reports have shown that cancerous phenotypes in the intestine are dependent on c-MYC target gene expression. Unfortunately, finding c-MYC inhibitors has proven difficult because c-MYC does not have a deep surface-binding pocket. Considering that c-MYC is maintained upregulated through β-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization, and since we have previously demonstrated that c-MYC transcriptional activation is affected by p38α as a β-catenin chromatin-associated kinase, here, we investigated p38α’s involvement in c-MYC protein stabilization in CRC. Interestingly, we found that p38α sustains c-MYC’s stability by preventing its ubiquitination and proteasomal degradation. Moreover, we showed that p38α inhibitors exhibit a synthetic lethality effect when used in combination with MEK inhibitors in CRC cells. Our findings identify p38α as a promising therapeutic target that acts on the pharmacologically “undruggable” c-MYC protein, with implications for countering c-MYC-mediated CRC proliferation, metastasization, and chemoresistance. c-MYC is one of the most important factors involved in colorectal cancer (CRC) initiation and progression; indeed, it is found to be upregulated in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC is maintained upregulated through β-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization. Our data demonstrate that p38α, a kinase involved in CRC metabolism and survival, contributes to c-Myc protein stability. Moreover, we show that p38α, like ERK, stabilizes c-MYC protein levels by preventing its ubiquitination. Of note, we found that p38α phosphorylates c-MYC and interacts with it both in vitro and in cellulo. Extensive molecular analyses in the cellular and in vivo models revealed that the p38α kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38α as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance.