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Oncogene:靶向表观遗传修饰 抗击晚期癌症

来源:生物谷 2015-06-19 14:11

2015年6月19日讯 /生物谷BIOON/ --近日,由Mayo Clinic肿瘤学家领导的国际研究小组发现了一种鉴定并有可能阻止许多晚期癌症继续进展的新方法,相关研究成果发表在国际学术期刊Oncogene上。
 
这篇文章主要对肾脏癌症及其转移进行了重点研究。但在之前一些对不同癌症类型中相同表观遗传印记的研究已经表明利用这种共同的信号途径或许可以帮助提高对晚期癌症的诊断率和治疗效果。
 
研究人员这样说道:“如果把晚期癌症看作一辆行驶的汽车,我们开发的大多数药物都瞄准了汽车轮胎的不同位置,但有时候会打偏,不能使这辆汽车完全停住。但我们认为我们已经发现了控制癌症的生物学引擎,通过这一机制或许能够将癌症阻止在它的跑道上。”
 
研究人员提到的这一机制是与转移性癌症中有关的一种表观遗传印记--H3K36me3,这种甲基化修饰的缺失可为鉴定侵袭性癌症,找到最好的个体治疗药物提供重要信息。这项研究首次将这一表观遗传印记与病人组织联系在一起,研究人员除了对肾脏癌症与H3K36me3缺失的关系进行了研究之外,还试图将这一机制扩展到其他类型的癌症中。
 
表观遗传学是一种复杂的生物学过程,细胞可通过阅读其基因及表观遗传修饰传递的信息,确定其将发育成哪种组织。癌细胞常常通过挟持细胞内正常的表观遗传机制,影响细胞的多种生物学过程,导致细胞更具侵袭性。因此,这项研究发现了H3K36me3在癌症发生发展中的重要作用,对于晚期癌症的诊断和治疗具有比较重要的意义。(生物谷Bioon.com)
 
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High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma
 
T H Ho1,2,17, I Y Park3,17, H Zhao4, P Tong4, M D Champion2,5, H Yan2,6, F A Monzon7,18, A Hoang8, P Tamboli9, A S Parker10, R W Joseph11, W Qiao12, K Dykema13, N M Tannir8, E P Castle14, R Nunez-Nateras14, B T Teh13, J Wang4, C L Walker3, M-C Hung15,16 and E Jonasch
 
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 SETD2knockout 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.
 
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