Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype.
Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype.
复制标题
DOI：
10.1002/mc.23301
复制
发表时间：
2021-07
影响因子：
4.6
通讯作者：
Eckert, Richard L.
中科院分区：
文献类型：
--
作者：
Ezeka, Geraldine;Adhikary, Gautam;Kandasamy, Sivaveera;Friedberg, Joseph S.;Eckert, Richard L.
间皮瘤是一种高度侵袭性的癌症的间皮瘤衬里是由暴露于石棉。手术切除后化疗是目前的治疗策略，但这是勉强成功，并导致耐药疾病。我们感兴趣的因素，保持积极的间皮瘤癌症表型作为治疗目标。蛋白质精氨酸甲基转移酶5（PRMT 5）与MEP 50辅因子协同作用以催化组蛋白3和4中关键精氨酸残基的对称二甲基化，其修饰染色质环境以改变肿瘤抑制基因和癌基因表达并增强癌细胞存活。我们的研究表明，PRMT 5或MEP 50损失减少H4 R3 me 2s形成，并且这与减少的癌细胞球状体形成、侵袭和迁移相关。用莱菔硫烷（SFN）（一种饮食来源的抗癌剂）治疗降低PRMT 5/MEP 50水平和H4 R3 me 2s形成，并抑制癌症表型。我们进一步表明，SFN治疗降低PRMT 5和MEP 50水平，并且这种降低是癌症表型的SFN抑制所必需的。SFN治疗还减少了与PRMT 5/MEP 50表达和活性降低相关的肿瘤形成。这些发现表明，SFN可能是一种有用的间皮瘤治疗剂，其至少部分地通过抑制PRMT 5/MEP 50功能来起作用。
Mesothelioma is a highly aggressive cancer of the mesothelial lining that is caused by exposure to asbestos. Surgical resection followed by chemotherapy is the current treatment strategy, but this is marginally successful and leads to drug resistant disease. We are interested in factors that maintain the aggressive mesothelioma cancer phenotype as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions in concert with the MEP50 cofactor to catalyze symmetric dimethylation of key arginine resides in histones 3 and 4 which modifies the chromatin environment to alter tumor suppressor and oncogene expression and enhance cancer cell survival. Our studies show that PRMT5 or MEP50 loss reduces H4R3me2s formation and that this is associated with reduced cancer cell spheroid formation, invasion and migration. Treatment with sulforaphane (SFN), a diet-derived anti-cancer agent, reduces PRMT5/MEP50 level and H4R3me2s formation, and suppresses the cancer phenotype. We further show that SFN treatment reduces PRMT5 and MEP50 levels and that this reduction is required for SFN suppression of the cancer phenotype. SFN treatment also reduces tumor formation which is associated with reduced PRMT5/MEP50 expression and activity. These findings suggest that SFN may be a useful mesothelioma treatment agent that operates, at least in part, via suppression of PRMT5/MEP50 function.
登录
查看更多内容
影响因子：
--
作者：
Adhikary G;Grun D;Alexander HR;Friedberg JS;Xu W;Keillor JW;Kandasamy S;Eckert RL
通讯作者：
Eckert RL
间皮瘤患者衍生出具有定义的BAP1突变的肿瘤异种移植物，这些突变模仿了人类恶性间皮瘤的分子特征。
影响因子：
3.8
作者：
Kalra N;Zhang J;Thomas A;Xi L;Cheung M;Talarchek J;Burkett S;Tsokos MG;Chen Y;Raffeld M;Miettinen M;Pastan I;Testa JR;Hassan R
通讯作者：
Hassan R
影响因子：
3.7
作者：
Ligr M;Patwa RR;Daniels G;Pan L;Wu X;Li Y;Tian L;Wang Z;Xu R;Wu J;Chen F;Liu J;Wei JJ;Lee P
通讯作者：
Lee P
影响因子：
5.2
作者：
Li, Yanyan;Zhang, Tao;Li, Xiaoqin;Zou, Peng;Schwartz, Steven J.;Sun, Duxin
通讯作者：
Sun, Duxin
影响因子：
4.6
作者：
Kerr C;Adhikary G;Grun D;George N;Eckert RL
通讯作者：
Eckert RL