RNF144A exerts tumor suppressor function in breast cancer through targeting YY1 for proteasomal degradation to downregulate GMFG expression

Abstract

AbstractRing finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, is an emerging tumor suppressor, but its underlying mechanism remains largely elusive. To address this issue, we used Affymetrix GeneChip Human Transcriptome Array 2.0 to profile gene expression in MDA-MB-231 cells stably expressing empty vector pCDH and Flag-RNF144A, and found that 128 genes were differentially expressed between pCDH- and RNF144A-expressing cells with fold change over 1.5. We further demonstrated that RNF144A negatively regulated the protein and mRNA levels of glial maturation factor γ (GMFG). Mechanistical investigations revealed that transcription factor YY1 transcriptionally activated GMFG expression, and RNF144A interacted with YY1 and promoted its ubiquitination-dependent degradation, thus blocking YY1-induced GMFG expression. Functional rescue assays showed that ectopic expression of RNF144A suppressed the proliferative, migratory, and invasive potential of breast cancer cells, and the noted effects were partially restored by re-expression of GMFG in RNF144A-overexpressing breast cancer cells. Collectively, these findings reveal that RNF144A negatively regulates GMFG expression by targeting YY1 for proteasomal degradation, thus inhibiting the proliferation, migration, and invasion of breast cancer cells.