Abstract
Abstract We reported earlier that heterozygous deletion of RUNX3 in the mouse induces adenoma in small intestine, mammary gland (1) and lung (2) and a precancerous stomach epithelium that is highly sensitive to a chemical carcinogen (3). We therefore propose that RUNX3 is a gatekeeper of cancer development (1). In our recent study on how RUNX3 inhibits early-stage cancer development in multiple tissues, we uncovered a previously unknown mode of MYC destabilization by RUNX3. From RNA sequencing, knockdown experiments, tumorigenic assays, protein interaction and ubiquitination studies, we show that the strong inhibitory effects of RUNX3 on proliferation and tumor growth may, in part, be attributed to its ability to promote MYC degradation. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix-loop-helix leucine zipper of MYC, resulting in the disruption of MYC/MAX interaction, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway (4). MYC inhibitor Omomyc, a short peptide comprising the b HLH LZ domain of MYC with 4 amino acid substitutions, is extremely effective in disrupting MYC/MAX interaction (5). RUNX3 appears to function similarly to Omomyc: is RUNX3 a Nature-designed Omomyc?
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