Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma.
Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma.
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表观基因组筛选表明，JMJD6在肾细胞癌中具有表观遗传易感性并介导舒尼替尼敏感性。
DOI：
10.1002/ctm2.328
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发表时间：
2021-03
影响因子：
10.6
通讯作者：
Xu D
中科院分区：
文献类型：
--
作者：
Zhang C;Lu X;Huang J;He H;Chen L;Liu Y;Wang H;Xu Y;Xing S;Ruan X;Yang X;Chen L;Xu D
异常表观遗传重编程是肾细胞癌（RCC）肿瘤发生和进展的标志。是否存在其他可作为治疗靶点的表观遗传脆弱性仍不清楚，也很有希望。在这里，我们将成簇的规则间隔的短回文重复序列功能筛选结果和多个RCC数据集相结合，以鉴定JMJD 6作为RCC中的有效靶标。JMJD 6表达与RCC患者的不良生存结局相关，并在体外和体内促进RCC进展。机制上，异常的p300导致高JMJD 6表达，其激活一系列致癌串扰。特别是，高通量测序数据显示，JMJD 6可以组装超级增强子，以驱动肾癌中的一系列身份基因，包括VEGFA，β-catenin和SRC。此外，这种JMJD 6介导的致癌作用可以被一种新型JMJD 6抑制剂（SKLB 325）抑制，这在RCC细胞、患者源性类器官模型和体内得到了进一步证实。考虑到JMJD 6签名和酪氨酸激酶抑制剂下游靶标之间可能的重叠串扰，靶向JMJD 6使RCC对舒尼替尼敏感，并且当它们组合在一起时具有协同作用。总的来说，这项研究表明，靶向JMJD 6是治疗RCC患者的有效方法。使用CRISPR/Cas9功能筛选数据和多个RCC数据集来鉴定JMJD 6为RCC中的表观遗传脆弱性。积累的JMJD 6主要构成改变致癌串扰的超级增强子，靶向JMJD 6是抑制RCC进展的有效方法。
Aberrant epigenetic reprogramming represents a hallmark of renal cell carcinoma (RCC) tumorigenesis and progression. Whether there existed other epigenetic vulnerabilities that could serve as therapeutic targets remained unclear and promising. Here, we combined the clustered regularly interspaced short palindromic repeats functional screening results and multiple RCC datasets to identify JMJD6 as the potent target in RCC. JMJD6 expression correlated with poor survival outcomes of RCC patients and promoted RCC progression in vitro and in vivo. Mechanistically, aberrant p300 led to high JMJD6 expression, which activated a series of oncogenic crosstalk. Particularly, high‐throughput sequencing data revealed that JMJD6 could assemble super‐enhancers to drive a list of identity genes in kidney cancer, including VEGFA, β‐catenin, and SRC. Moreover, this JMJD6‐mediated oncogenic effect could be suppressed by a novel JMJD6 inhibitor (SKLB325), which was further demonstrated in RCC cells, patient‐derived organoid models, and in vivo. Given the probable overlapped crosstalk between JMJD6 signature and tyrosine kinase inhibitors downstream targets, targeting JMJD6 sensitized RCC to sunitinib and was synergistic when they were combined together. Collectively, this study indicated that targeting JMJD6 was an effective approach to treat RCC patients. The CRISPR/Cas9 functional screening data and multiple RCC datasets were used to identify JMJD6 as the epigenetic vulnerability in RCC. Accumulated JMJD6 mainly constitutes super‐enhancers to alter oncogenic crosstalk and targeting JMJD6 was an effective approach to suppress RCC progression.
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影响因子：
16
作者：
Gao WW;Xiao RQ;Zhang WJ;Hu YR;Peng BL;Li WJ;He YH;Shen HF;Ding JC;Huang QX;Ye TY;Li Y;Liu ZY;Ding R;Rosenfeld MG;Liu W
通讯作者：
Liu W
JMJD6 通过新型酪氨酸激酶活性调节组蛋白 H2A.X 磷酸化并促进三阴性乳腺癌细胞自噬
影响因子：
8
作者：
Liu, Yan;Long, Yue-Hong;Zhang, Xiao-Jun
通讯作者：
Zhang, Xiao-Jun
影响因子：
64.5
作者：
Liu W;Ma Q;Wong K;Li W;Ohgi K;Zhang J;Aggarwal A;Rosenfeld MG
通讯作者：
Rosenfeld MG
影响因子：
16
作者：
Lambert, Jean-Philippe;Picaud, Sarah;Gingras, Anne-Claude
通讯作者：
Gingras, Anne-Claude
基因组尺度CRISPR-CAS9敲除和转录激活筛选。
影响因子：
14.8
作者：
Joung J;Konermann S;Gootenberg JS;Abudayyeh OO;Platt RJ;Brigham MD;Sanjana NE;Zhang F
通讯作者：
Zhang F