SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling.
SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling.
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SHANK2 是一种经常扩增的癌基因，在调节 Hippo 信号传导方面具有进化上保守的作用
DOI：
10.1007/s13238-020-00742-6
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发表时间：
2021-03
期刊：
影响因子：
21.1
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Xu L;Li P;Hao X;Lu Y;Liu M;Song W;Shan L;Yu J;Ding H;Chen S;Yang A;Zeng YA;Zhang L;Jiang H
Hippo通路的功能障碍使细胞能够逃避接触抑制，并为癌性过度生长提供优势。然而，对于很大一部分人类癌症，Hippo信号是如何被干扰的仍然是未知的。为了回答这个问题，我们对果蝇中影响Hippo通路的基因进行了全基因组筛选，并将命中基因与人类癌症基因组进行了交叉引用。在我们的筛选中，Prosap被确定为Hippo途径的一种新型调节剂，可有效影响组织生长。有趣的是，Prosap的哺乳动物同源物SHANK 2是11 q13上最常扩增的基因，11 q13是人类癌症中的主要肿瘤扩增子。该11 q13扩增子中的基因扩增谱清楚地表明了SHANK 2扩增的选择压力。更重要的是，在整个人类癌症基因组中，SHANK 2是不位于Myc扩增子内的最频繁扩增的基因。在多种人类细胞系中的进一步研究证实，SHANK 2过表达通过与LATS 1激活剂竞争性结合导致Hippo信号转导失调，并且作为潜在的致癌基因，SHANK 2促进体内细胞转化和肿瘤形成。在具有失调的Hippo通路的癌细胞系中，SHANK 2的消耗恢复Hippo信号传导并停止细胞增殖。总之，这些结果表明，SHANK 2是一种进化上保守的Hippo通路调节因子，通常在人类癌症中扩增，并有效地促进癌症。我们的研究首次阐明了SHANK 2基因的致癌功能，SHANK 2是人类癌症中最常见的扩增基因之一。此外，考虑到在正常成人组织中，SHANK 2的表达主要限于神经系统，SHANK 2可能是抗癌治疗的一个有趣的靶点。本文的在线版本（10.1007/s13238-020-00742-6）包含补充材料，可供授权用户使用。
Dysfunction of the Hippo pathway enables cells to evade contact inhibition and provides advantages for cancerous overgrowth. However, for a significant portion of human cancer, how Hippo signaling is perturbed remains unknown. To answer this question, we performed a genome-wide screening for genes that affect the Hippo pathway in Drosophila and cross-referenced the hit genes with human cancer genome. In our screen, Prosap was identified as a novel regulator of the Hippo pathway that potently affects tissue growth. Interestingly, a mammalian homolog of Prosap, SHANK2, is the most frequently amplified gene on 11q13, a major tumor amplicon in human cancer. Gene amplification profile in this 11q13 amplicon clearly indicates selective pressure for SHANK2 amplification. More importantly, across the human cancer genome, SHANK2 is the most frequently amplified gene that is not located within the Myc amplicon. Further studies in multiple human cell lines confirmed that SHANK2 overexpression causes deregulation of Hippo signaling through competitive binding for a LATS1 activator, and as a potential oncogene, SHANK2 promotes cellular transformation and tumor formation in vivo. In cancer cell lines with deregulated Hippo pathway, depletion of SHANK2 restores Hippo signaling and ceases cellular proliferation. Taken together, these results suggest that SHANK2 is an evolutionarily conserved Hippo pathway regulator, commonly amplified in human cancer and potently promotes cancer. Our study for the first time illustrated oncogenic function of SHANK2, one of the most frequently amplified gene in human cancer. Furthermore, given that in normal adult tissues, SHANK2’s expression is largely restricted to the nervous system, SHANK2 may represent an interesting target for anticancer therapy. The online version of this article (10.1007/s13238-020-00742-6) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Chang L;Azzolin L;Di Biagio D;Zanconato F;Battilana G;Lucon Xiccato R;Aragona M;Giulitti S;Panciera T;Gandin A;Sigismondo G;Krijgsveld J;Fassan M;Brusatin G;Cordenonsi M;Piccolo S
通讯作者：
Piccolo S
影响因子：
11.4
作者：
Arash, Emad Heidary;Song, Ki Myung;Attisano, Liliana
通讯作者：
Attisano, Liliana
影响因子：
4
作者：
Gumbiner, Barry M.;Kim, Nam-Gyun
通讯作者：
Kim, Nam-Gyun
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影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai
影响因子：
5.3
作者：
Hung, Albert Y.;Futai, Kensuke;Sheng, Morgan
通讯作者：
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