Cullin 4B (CUL4B) is a component of the Cullin4B-Ring E3 ligase complex (CRL4B) that functions in proteolysis and is implicated in tumorigenesis. Here, we report that CRL4B is associated with histone methyltransferase SUV39H1, heterochromatin protein 1 (HP1) and DNA methyltransferases 3A (DNMT3A). We showed that CRL4B, through catalyzing H2AK119 monoubiquitination, facilitates H3K9 tri-methylation and DNA methylation, two key epigenetic modifications involved in DNA methylation-based gene silencing. Depletion of CUL4B resulted in loss of not only H2AK119 monoubiquitination but also H3K9 trimethylation and DNA methylation, leading to derepression of a collection of genes, including the tumor suppressor IGFBP3. We demonstrated that CUL4B promotes cell proliferation and invasion, which are consistent with a tumorigenic phenotype, at least partially by repressing IGFBP3. We found that the expression of CUL4B is markedly upregulated in samples of human cervical carcinoma and is negatively correlated with the expression of IGFBP3. Our experiments unveiled a coordinated action between histone ubiquitination/methylation and DNA methylation in transcription repression, providing a mechanism for CUL4B in tumorigenesis.

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The transcription factor GATA3 is a key regulator of mammary gland development and a definitive marker of luminal breast cancer. However, the molecular mechanisms underlying the role of GATA3 in breast carcinogenesis is still not fully understood. We report here that GATA3 promotes cell proliferation and tumorigenesis by facilitating the G1/S transition through its transcription regulation of the CCND1 gene in breast cancer cells. We found that GATA3 is physically associated with poly-ADP ribose polymerase-1 (PARP1), an enzyme modifying nuclear proteins by poly(ADP-ribosyl)ation. We showed that PARP1 acts as a transcription coactivator for GATA3 in breast cancer cells and demonstrated that GATA3 cooperates with PARP1 in transactivation of the CCND1 gene. We demonstrated that PARP1 competes with linker histone H1 to maintain a transcriptional competent chromatin environment for CCND1 gene. Our results unveiled a molecular basis for the coordinated regulation between GATA3 and PARP1 in transcription activation, providing a mechanism for GATA3 in breast carcinogenesis.

Current evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have emerged as novel drugs for preventing the development of atrial fibrillation (AF). A meta-analysis was performed of 26 randomized controlled clinical trials evaluating the effect of ACEIs or ARBs on the prevention of AF. Overall, ACEIs and ARBs revealed statistically significant preventive effects on AF (odds ratio (OR), 0.65; 95% confidence interval (CI), 0.55-0.76). The preventive effect was similar in the two classes of drugs (ACEI: OR, 0.68; ARB: OR, 0.69). ACEIs and ARBs showed greater preventive effects on recurrent AF (OR, 0.45; 95% CI, 0.31-0.65) than on new-onset AF (OR, 0.80; 95% CI, 0.70-0.92). Prevention was greatest in patients with AF who were receiving amiodarone as a basic treatment drug (OR, 0.35; 95% CI, 0.26-0.48). In patients with heart failure, there appeared to be a large effect (OR, 0.497), but the credible interval (CrI) limits were wide (95% CrI, 0.187-1.161).