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.
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.
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Qinqin
Q
Yu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Yanqing
Y
Liu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Xiaoli
X
Zheng
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Qianying
Q
Zhu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Zhuowei
Z
Shen
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Hua
H
Wang
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Huadong
H
He
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Nengming
N
Lin
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Huidi
H
Jiang
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.).
Lushan
L
Yu
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Q.Y., Y.L., X.Z., Q.Z., Z.S., H.J., L.Y., S.Z.); Department of Urology, Cancer Hospital of Zhejiang Province, Hangzhou, China (H.W.); and Department of Urology, Hangzhou First People's Hospital, Hangzhou, China (H.H., N.L.) zengsu@zju.edu.cn.
Su
S
Zeng
D000107:Acetylation; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D014158:Transcription, Genetic
D006657:Histones; D027701:Organic Cation Transport Proteins; C521870:SLC47A2 protein, human; D008239:Lysine