Histone H3 Lysine 4 Trimethylation, Lysine 27 Trimethylation, and Lysine 27 Acetylation Contribute to the Transcriptional Repression of Solute Carrier Family 47 Member 2 in Renal Cell Carcinoma

作者：Yu, Qinqin; Liu, Yanqing; Zheng, Xiaoli; Zhu, Qianying; Shen, Zhuowei; Wang, Hua; He, Huadong; Lin, Nengming; Jiang, Huidi; Yu, Lushan; Zeng, Su^*

来源：Drug Metabolism and Disposition, 2017, 45(1): 109-117.

DOI：10.1124/dmd.116.073734

• EMBRYONIC STEM-CELLS
• FUNCTIONAL-CHARACTERIZATION
• PROGNOSTIC RELEVANCE
• GENETIC-VARIANTS
• HUMAN MULTIDRUG
• METHYLATION
• METFORMIN
• MATE2-K
• CANCER
• PHARMACOKINETICS

In recent years, finding effective biomarkers for identifying early stage cancer and predicating prognosis is crucial for renal cell carcinoma (RCC) diagnosis and treatment. In this study, a dramatic decrease of the solute carrier family 47 member 2 (SLC47A2) mRNA in RCC comparing with the paired adjacent nontumor tissues from patients at low Tumor Node Metastasis stage was observed. Thus, patients with SLC47A2 transcriptional repression are susceptible to RCC. Little is known about the regulation mechanism of SLC47A2. We found that it was a bivalent gene that was enriched with both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3). Loss of mixed lineage leukemia 1 binding at the gene promoter caused decreased H3K4me3 enrichment and H3K4me3/H3K27me3 ratio, and subsequently repressed the expression of SLC47A2. These two epigenetic markers modulated the expression of SLC47A2 simultaneously, suggesting the regulation pattern for bivalent genes. Histone H3 lysine 27 acetylation also contributed to the expression of SLC47A2. An E2F1-histone deacetylase 10 complex catalyzed deacetylation of H3K27, then prevented the enrichment of H3K4me3, and finally reduced SLC47A2 expression. Consequently, the combined effect of all these factors determined SLC47A2 transcriptional repression in RCC tissues.

• 出版日期2017-1
• 单位浙江省肿瘤医院; 杭州市第一人民医院; 浙江大学