CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis.

We reported that Cullin4B-Ring E3 ligase complex (CRL4B) is physically associated with Polycomb-repressive complex 2 (PRC2). We showed that CRL4B possesses an intrinsic transcription repressive activity by promoting H2AK119 monoubiquitination. Ablation of Cul4b or depletion of CUL4B, the main component of CRL4B, resulted in loss of not only H2AK119 monoubiquitination but also H3K27 trimethylation, leading to derepression of target genes that are critically involved in cell growth and migration. We demonstrated that CUL4B promotes cell proliferation, invasion, and tumorigenesis in vitro and in vivo and found that its expression is markedly upregulated in various human cancers. Our data indicate that CUL4B promotes tumorigenesis, supporting the pursuit of CUL4B as a target for cancer therapy.