High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma.

Autor: Ho TH; Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Park IY; Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA., Zhao H; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tong P; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Champion MD; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, AZ, USA., Yan H; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.; Department of Biomedical Statistics and Informatics, Rochester, MN, USA., Monzon FA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA., Hoang A; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tamboli P; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Parker AS; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA., Joseph RW; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Qiao W; Division of Quantitative Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dykema K; Center for Cancer Genomics and Computational Biology, Van Andel Institute, Grand Rapids, MI, USA., Tannir NM; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Castle EP; Department of Urology, Mayo Clinic, Scottsdale, AZ, USA., Nunez-Nateras R; Department of Urology, Mayo Clinic, Scottsdale, AZ, USA., Teh BT; Center for Cancer Genomics and Computational Biology, Van Andel Institute, Grand Rapids, MI, USA., Wang J; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Walker CL; Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA., Hung MC; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan., Jonasch E; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2016 Mar 24; Vol. 35 (12), pp. 1565-74. Date of Electronic Publication: 2015 Jun 15.
DOI: 10.1038/onc.2015.221
Abstrakt: Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.
Databáze: MEDLINE
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