Identification of hepatocellular carcinoma subtypes based on PcG-related genes and biological relevance with cancer cells.
Identification of hepatocellular carcinoma subtypes based on PcG-related genes and biological relevance with cancer cells.
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基于PcG相关基因及其与癌细胞生物学相关性的肝细胞癌亚型鉴定
DOI：
10.1186/s13148-022-01393-6
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发表时间：
2022-12-24
影响因子：
5.7
通讯作者：
Qu, Kai
中科院分区：
文献类型：
--
作者：
Fu, Yunong;Yang, Kaibo;Wu, Kunjin;Wang, Hai;Li, Qinglin;Zhang, Fengping;Yang, Kun;Yao, Qing;Ma, Xiaohua;Deng, Yujie;Zhang, Jingyao;Liu, Chang;Qu, Kai
关键词：
背景肝细胞癌是一种广泛的异质性疾病，表观遗传因素参与了其发病机制。聚梳组(Polycomb group，PcG)蛋白是一组组成各种大分子机器调节表观遗传格局的亚基，与肿瘤表型有关，并有可能发展一种肝癌的分子分类。结果基于DNA甲基化、mRNA表达和PcG相关基因拷贝数的多组学数据分析，我们建立了肝癌的表观遗传学分类系统，将肝癌患者分为两个亚组，结果明显不同。比较这两个表观遗传亚群，我们发现了不同的代谢特征，这些特征与多梳抑制复合体1/2(Prc1/2)的表观遗传调控有关。此外，我们的实验证明，抑制PcG复合体可以增强肝癌细胞的脂代谢，降低其抵御葡萄糖缺乏的能力。此外，我们还验证了A组肝癌细胞对化疗的低敏感性，并发现抑制Prc1/2在体内和体外都能增强肝癌细胞对奥沙利铂的敏感性。最后，我们发现A组CBX2的异常上调和CBX2的上调与肝细胞癌患者的预后不良有关。此外，我们还发现操作CBX2会影响H3K27me3和H3AK119ub的水平。我们的研究提供了一个基于PcG相关基因数据的新的分子分类系统，并从实验上验证了两个亚组的肝癌的生物学特征。我们的发现支持多梳复合体靶向策略来抑制肝癌的进展，其中CBX2可能是一个可行的治疗靶点。
BackgroundHepatocellular carcinoma (HCC) is an extensive heterogeneous disease where epigenetic factors contribute to its pathogenesis. Polycomb group (PcG) proteins are a group of subunits constituting various macro-molecular machines to regulate the epigenetic landscape, which contributes to cancer phenotype and has the potential to develop a molecular classification of HCC.ResultsHere, based on multi-omics data analysis of DNA methylation, mRNA expression, and copy number of PcG-related genes, we established an epigenetic classification system of HCC, which divides the HCC patients into two subgroups with significantly different outcomes. Comparing these two epigenetic subgroups, we identified different metabolic features, which were related to epigenetic regulation of polycomb-repressive complex 1/2 (PRC1/2). Furthermore, we experimentally proved that inhibition of PcG complexes enhanced the lipid metabolism and reduced the capacity of HCC cells against glucose shortage. In addition, we validated the low chemotherapy sensitivity of HCC in Group A and found inhibition of PRC1/2 promoted HCC cells’ sensitivity to oxaliplatin in vitro and in vivo. Finally, we found that aberrant upregulation of CBX2 in Group A and upregulation of CBX2 were associated with poor prognosis in HCC patients. Furthermore, we found that manipulation of CBX2 affected the levels of H3K27me3 and H2AK119ub.ContributionsOur study provided a novel molecular classification system based on PcG-related genes data and experimentally validated the biological features of HCC in two subgroups. Our founding supported the polycomb complex targeting strategy to inhibit HCC progression where CBX2 could be a feasible therapeutic target.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1186/s13046-022-02297-2
发表时间：
2022-03-24
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Braghini MR;Lo Re O;Romito I;Fernandez-Barrena MG;Barbaro B;Pomella S;Rota R;Vinciguerra M;Avila MA;Alisi A
通讯作者：
Alisi A
影响因子：
51.1
作者：
Gounder, Mrinal;Schoffski, Patrick;Stacchiotti, Silvia
通讯作者：
Stacchiotti, Silvia
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V
蛋白质组学特征鉴定了肝内胆管癌的临床相关亚组。
影响因子：
50.3
作者：
Dong, Liangqing;Lu, Dayun;Fan, Jia
通讯作者：
Fan, Jia