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Asangani等合作研究组在研究中取得进展。他们的最新研究揭示了NSD2是AR/FOXA1新型增强体促进前列腺肿瘤发生的必要亚基。相关论文于2024年9月9日发表在《自然—遗传学》杂志上。</p> <p> 该研究团队发现肿瘤特异性雄激素受体增强子，严重依赖于NSD2的H3K36二甲基转移酶活性。NSD2在前列腺癌中异常诱导表达，其失活会破坏超过65%的AR（雄激素受体）染色质结合区域，从而削弱AR的转录激活潜力。</p> <p> NSD2依赖性AR位点独特地包含嵌合的FOXA1:AR半基序，这些位点专门构成了，从患者标本中定义的肿瘤特异性AR增强子回路。NSD2的失活还导致对NSD1旁系同源物的依赖性增加，而双靶向NSD1/2的PROTAC降解剂，在AR依赖的前列腺癌模型中具有优先的细胞毒性。</p> <p> 总之，研究团队将NSD2描述为一个重要的AR新型增强体亚基，使其具有致癌活性，并将NSD1/2定位为晚期前列腺癌的可行共同靶点。</p> <p> 据了解，雄激素受体(AR)是一种配体应答转录因子，驱动前列腺腔上皮的终末分化。相比之下，在起源于这些细胞的肿瘤中，雄激素受体染色质占用被广泛重编程以激活恶性表型，其分子机制尚不清楚。</p> <p> <strong>附：英文原文</strong></p> <p> Title: NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis</p> <p> Author: Parolia, Abhijit, Eyunni, Sanjana, Verma, Brijesh Kumar, Young, Eleanor, Liu, Yihan, Liu, Lianchao, George, James, Aras, Shweta, Das, Chandan Kanta, Mannan, Rahul, ur Rasool, Reyaz, Mitchell-Velasquez, Erick, Mahapatra, Somnath, Luo, Jie, Carson, Sandra E., Xiao, Lanbo, Gajjala, Prathibha R., Venkatesh, Sharan, Jaber, Mustapha, Wang, Xiaoju, He, Tongchen, Qiao, Yuanyuan, Pang, Matthew, Zhang, Yuping, Tien, Jean Ching-Yi, Louw, Micheala, Alhusayan, Mohammed, Cao, Xuhong, Su, Fengyun, Tavana, Omid, Hou, Caiyun, Wang, Zhen, Ding, Ke, Chinnaiyan, Arul M., Asangani, Irfan A.</p> <p> Issue&Volume: 2024-09-09</p> <p> Abstract: Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer.</p> <p> DOI: 10.1038/s41588-024-01893-6</p> <p> Source: <a href="https://www.nature.com/articles/s41588-024-01893-6">https://www.nature.com/articles/s41588-024-01893-6</a></p> </p> <div class="remarks">期刊信息</div> <div class="dd"><p> <span style="font-weight: bold;">Nature Genetics：</span>《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307<br /> <span style="font-weight: bold;">官方网址：</span><a href="https://www.nature.com/ng/" target="_blank">https://www.nature.com/ng/</a><br /> <span style="font-weight: bold;">投稿链接：</span><a href="https://mts-ng.nature.com/cgi-bin/main.plex" target="_blank">https://mts-ng.nature.com/cgi-bin/main.plex</a></p> </div> </div> </div> <style> #footer{ background:#890f0e; text-align:center; padding:10px; color:#FFF; font-size:12px;} #footer a{color:#FFF; font-size:12px;} </style> <div id="footer"><a href="http://www.sciencenet.cn/aboutus/" target="_blank">关于我们</a> | <a href="http://www.sciencenet.cn/shengming.aspx" target="_blank">网站声明</a> | <a href="http://www.sciencenet.cn/tiaokuang.aspx" target="_blank">服务条款</a> | <a href="http://www.sciencenet.cn/contact.aspx" target="_blank">联系方式</a> | <a href="http://www.sciencenet.cn/RSS.aspx">RSS</a> | <a href="mailto:jubao@stimes.cn">举报</a> | <a href="https://stimes.sciencenet.cn/">中国科学报社</a> <br> <a href="https://beian.miit.gov.cn" target="_blank" > 京ICP备07017567号-12 </a> 互联网新闻信息服务许可证10120230008  京公网安备 11010802032783<br>Copyright @ 2007-<script type="text/javascript">var Date22 = new Date();var year22 = Date22.getFullYear();document.write(year22);</script> 中国科学报社 All Rights Reserved<br> 地址：北京市海淀区中关村南一条乙三号  邮箱：blog@stimes.cn <br> <span style="display:none"> <script type="text/javascript"> var _bdhmProtocol = (("https:" == document.location.protocol) ? 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