USP49-Mediated Histone H2B Deubiquitination Regulates HCT116 Cell Proliferation through MDM2-p53 Axis

Posttranslational histone modifications play important roles in regulating chromatin structure and transcriptional regulation. Histone H2B monoubiquitination (H2Bub) is an essential regulator for transcriptional elongation and ongoing transcription. Here, we report that USP49, as a histone H2B deubiquitinase, is involved in HCT116 cell proliferation through modulating MDM2-p53 pathway genes. USP49 knockout contributes to increased HCT116 cell proliferation and migration. Importantly, USP49 knockout stimulated MDM2 transcriptional levels and then inhibited the mRNA levels of TP53 target genes. Conversely, the overexpression of USP49 suppressed MDM2 gene expression and then promoted TP53 target genes. Moreover, chromatin immunoprecipitation revealed that USP49 directly bound to the promoter of the MDM2 gene. USP49 knockout increased H2Bub enrichment at the MDM2 gene, whereas USP49 overexpression downregulated the H2Bub level at the MDM2 gene. Therefore, our findings indicated that USP49-mediated H2B deubiquitination controls the transcription of MDM2-p53 axis genes in the process of HCT116 cell proliferation.