Tianshu Yang

Abstract HMGB1 is an architectural chromatin-binding protein that can be released actively by activated cells or passively by dying cells and can serve as a DAMP molecule to drive the pathogenesis of inflammatory and angiogenic diseases. Through TLR4 and RAGE signaling pathways, HMGB1 could regulate vascular growth in vivo and in vitro through diverse mechanisms, including induction of proangiogenic cytokine release and activation of ECs, macrophages, EPCs, and mesoangioblasts, all of which could contribute to vessel formation. Accordingly, HMGB1 plays a significant role in many angiogenesis-related conditions, such as tumors, PDR, wound-healing, and ischemia-induced angiogenesis. In this review, we focus on the regulatory role of HMGB1 in angiogenesis and recent progress in therapeutic strategies targeting HMGB1.

Breast cancer is one of the leading causes of cancer-associated mortality in women worldwide and has become a major public health problem. Although the definitive cause of breast cancer is not known, many genes sensitive to breast cancer have been detected using advanced technologies. Our study identified 3301 differentially expressed lncRNAs and mRNAs between tumor and normal samples from The Cancer Genome Atlas database. Based on the gene expression analysis and clinical traits as well as weighted gene co-expression network analysis, the co-expression Brown module was found to be key for breast cancer prognosis. A total of 453 genes in the Brown module were used for functional enrichment, protein-protein interaction analysis, lncRNA-miRNA-mRNA ceRNA network, and lncRNA-RNA binding protein-mRNA network construction. GRM4, SSTR2, PARD6B, PRR15, COX6C, and lncRNA DSCAM-AS1 were the hub genes according to protein-protein interaction, lncRNA-miRNA-mRNA and lncRNA-RNA binding protein-mRNA network. Their high expression was found to be correlated with breast cancer development, according to multiple databases. In conclusion, this study provides a framework of the co-expression gene modules of breast cancer and identifies several important biomarkers in breast cancer development and prognosis.

Runt-related transcription factor 2 (RUNX2) is an osteogenesis-related transcription factor that has emerged as a prominent transcription repressing factor in carcinogenesis. However, the role of RUNX2 in breast cancer metastasis remains poorly understood. Here, we show that RUNX2 recruits the metastasis-associated 1 (MTA1)/NuRD and the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex, which catalyzes the histone deacetylation and ubiquitylation. Genome-wide analysis of the RUNX2/NuRD(MTA1)/CRL4B complex targets identified a cohort of genes including peroxisome proliferator-activated receptor alpha (PPARα) and superoxide dismutase 2 (SOD2), which are critically involved in cell growth, epithelial-to-mesenchymal transition (EMT) and invasion. We demonstrate that the RUNX2/NuRD(MTA1)/CRL4B complex promotes the proliferation, invasion, tumorigenesis, bone metastasis, cancer stemness of breast cancer in vitro and in vivo. Strikingly, RUNX2 expression is upregulated in multiple human carcinomas, including breast cancer. Our study suggests that RUNX2 is a promising potential target for the future treatment strategies of breast cancer.

The biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.

Epigenetics studies heritable genomic modifications that occur with the participation of epigenetic modifying enzymes but without alterations of the nucleotide structure. Small-molecule inhibitors of these epigenetic modifying enzymes are known as epigenetic drugs (epi-drugs), which can cause programmed death of tumor cells by affecting the cell cycle, angiogenesis, proliferation, and migration. Epi-drugs include histone methylation inhibitors, histone demethylation inhibitors, histone deacetylation inhibitors, and DNA methylation inhibitors. Currently, epi-drugs undergo extensive development, research, and application. Although epi-drugs have convincing anti-tumor effects, the patient's sensitivity to epi-drug application is also a fundamental clinical issue. The development and research of biomarkers for epi-drugs provide a promising direction for screening drug-sensitive patients. Here, we review the predictive biomarkers of 12 epi-drugs as well as the progress of combination therapy with chemotherapeutic drugs or immunotherapy. Further, we discuss the improvement in the development of natural ingredients with low toxicity and low side effects as epi-drugs.