Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.
Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.
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SMYD2甲基转移酶诱导的细胞骨架重塑促进乳腺癌转移。
DOI：
10.1038/s41421-023-00644-x
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发表时间：
2024-01-31
期刊：
影响因子：
33.5
通讯作者：
Reynoird, Nicolas
中科院分区：
文献类型：
--
作者：
Casanova, Alexandre G.;Roth, Gael S.;Hausmann, Simone;Lu, Xiaoyin;Bischoff, Ludivine J. M.;Froeliger, Emilie M.;Belmudes, Lucid;Bourova-Flin, Ekaterina;Flores, Natasha M.;Benitez, Ana Morales;Chasan, Tourkian;Caporicci, Marcello;Vayr, Jessica;Blanchet, Sandrine;Ielasi, Francesco;Rousseaux, Sophie;Hainaut, Pierre;Gozani, Or;Le Romancer, Muriel;Coute, Yohann;Palencia, Andres;Mazur, Pawel K.;Reynoird, Nicolas
对现有疗法难治的恶性形式的乳腺癌仍然是一个主要的未解决的健康问题，主要是由于转移性扩散。更好地了解起作用的机制将为预防乳腺癌细胞分散的替代治疗提供更好的见解。在这里，我们确定赖氨酸甲基转移酶SMYD 2作为临床上可操作的乳腺癌转移的主调节因子。虽然SMYD 2在侵袭性乳腺癌中过表达，但我们注意到它不是原发性肿瘤生长所必需的。然而，乳腺上皮特异性SMYD 2消融通过阻断原发性肿瘤细胞转移的能力来增加小鼠的总体存活率。从机制上讲，我们将BCAR 3鉴定为乳腺癌细胞中SMYD 2的真正生理底物。在赖氨酸K334（K334 me 1）处单甲基化的BCAR 3被FMNL蛋白中存在的新型甲基结合结构域识别。这些肌动蛋白细胞骨架调节因子通过SMYD 2甲基化信号在细胞边缘募集并调节板状伪足特性。BCAR 3甲基化受损的乳腺癌细胞在体外失去迁移和侵袭能力，并且在体内促进转移方面无效。值得注意的是，SMYD 2药理学抑制有效地削弱了来自基因工程小鼠的乳腺癌细胞、PDX和侵袭性乳腺肿瘤的转移扩散。这项研究为通过靶向SMYD 2-BCAR 3-FMNL轴来预防恶性乳腺癌转移进展的创新治疗提供了理论基础。
Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.
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影响因子：
4.8
作者：
Makkinje A;Near RI;Infusini G;Vanden Borre P;Bloom A;Cai D;Costello CE;Lerner A
通讯作者：
Lerner A
影响因子：
7.3
作者：
Eggert E;Hillig RC;Koehr S;Stöckigt D;Weiske J;Barak N;Mowat J;Brumby T;Christ CD;Ter Laak A;Lang T;Fernandez-Montalvan AE;Badock V;Weinmann H;Hartung IV;Barsyte-Lovejoy D;Szewczyk M;Kennedy S;Li F;Vedadi M;Brown PJ;Santhakumar V;Arrowsmith CH;Stellfeld T;Stresemann C
通讯作者：
Stresemann C
影响因子：
21.3
作者：
Esposito M;Fang C;Cook KC;Park N;Wei Y;Spadazzi C;Bracha D;Gunaratna RT;Laevsky G;DeCoste CJ;Slabodkin H;Brangwynne CP;Cristea IM;Kang Y
通讯作者：
Kang Y
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.4
作者：
Casabona, Maria G.;Vandenbrouck, Yves;Coute, Yohann
通讯作者：
Coute, Yohann