小柯机器人

美国斯坦福大学Or Gozani等研究人员合作发现，NSD3组蛋白甲基化活性升高驱动鳞状细胞肺癌。相关论文于2021年2月3日在线发表在《自然》杂志上。

研究人员发现，组蛋白H3赖氨酸36（H3K36）甲基转移酶NSD3（该基因位于8p11-12扩增子中）是肺鳞状细胞癌（LUSC）肿瘤发生的关键调控因子。与其他8p11-12候选LUSC驱动程序相比，NSD3表达的增加与其基因扩增高度相关。在LUSC小鼠模型中，NSD3的敲除而不是FGFR1的敲除减弱了肿瘤的生长并延长了生存期。

研究人员确定一个LUSC相关的变体NSD3（T1232A），可在体外和体内对H3K36（H3K36me2）的二甲基化显示出催化活性的增加。结构动力学分析表明，T1232A取代引发了整个NSD3催化域的局部迁移率变化，从而减轻了自抑制作用并增加了H3底物的可及性。NSD3（T1232A）在体内的表达加速了LUSC小鼠模型的肿瘤发生并降低了总生存期。NSD3（T1232A）介导的H3K36me2重塑了染色质景观，进而促进致癌基因表达。

此外，NSD3以一种依赖于其催化活性的方式促进了人类气管支气管细胞的转化和人类LUSC细胞系的荷瘤生长。包含NSD3扩增或NSD3（T1232A）编码变体的原发LUSC患者来源的异种移植物中NSD3的敲除减弱了小鼠的肿瘤生长。最后，NSD3调控的LUSC来源异种移植物对溴结构域抑制高度敏感。因此，这项工作将NSD3鉴定为LUSC中主要的8p11–12扩增子相关致癌驱动因子，并表明NSD3依赖性使得LUSC在治疗上易受溴结构域抑制。 

据介绍，染色体区域8p11-12的扩增是一种常见的遗传改变，与LUSC的发病有关。FGFR1基因是该区域内肿瘤发生的主要候选驱动因素。但是，以FGFR1抑制作为靶向治疗的临床试验并未成功。

附：英文原文

Title: Elevated NSD3 histone methylation activity drives squamous cell lung cancer

Author: Gang Yuan, Natasha M. Flores, Simone Hausmann, Shane M. Lofgren, Vladlena Kharchenko, Maria Angulo-Ibanez, Deepanwita Sengupta, Xiaoyin Lu, Iwona Czaban, Dulat Azhibek, Silvestre Vicent, Wolfgang Fischle, Mariusz Jaremko, Bingliang Fang, Ignacio I. Wistuba, Katrin F. Chua, Jack A. Roth, John D. Minna, Ning-Yi Shao, ukasz Jaremko, Pawel K. Mazur, Or Gozani

Issue&Volume: 2021-02-03

Abstract: Amplification of chromosomal region 8p11–12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1,2,3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11–12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11–12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11–12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11–12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.

DOI: 10.1038/s41586-020-03170-y

Source: https://www.nature.com/articles/s41586-020-03170-y

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