PDCD11 Stabilizes C‐MYC Oncoprotein by Hindering C‐MYC‐SKP2 Negative Feedback Loop to Facilitate Progression of p53‐Mutant Breast and Colon Malignancies

C-MYC is a proto-oncoprotein whose dysregulation triggers tumorigenesis and tumor progression in ≈70% of cancer cases. It is presently demonstrated that aberrantly upregulated MYC is caused by the overexpressed and "extra-nucleolar" PDCD11 in p53-mutant breast and colon cancer cells, which is highly correlated to tumor progression, metastasis, and recurrence. In the nucleoplasm, PDCD11 binds to the TAD of C-MYC to prevent SKP2, a transcriptional target of C-MYC as well as one of the major E3 ligase components targeting C-MYC, from interacting with and ubiquitinating C-MYC in feedback. The ensuing stabilized C-MYC activates downstream signaling to facilitate the cellular G1/S transition, proliferation, and migration. PDCD11 silencing restores SKP2-mediated C-MYC degradation, thereby remarkably suppressing tumor growth and metastasis in nude mice. These findings highlight PDCD11 as a novel C-MYC partner and thereby offer a potential therapeutic rationale to challenge PDCD11-mediated "pro-stabilization" effect on C-MYC, a widely considered "undruggable" target, to combat C-MYC-driven malignancies with p53 mutation.