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

Abstract 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.