CRISPR/Cas9-mediated Knockout of SIRT6 Imparts Remarkable Antiproliferative Response in Human Melanoma Cells in vitro and in vivo.
CRISPR/Cas9-mediated Knockout of SIRT6 Imparts Remarkable Antiproliferative Response in Human Melanoma Cells in vitro and in vivo.
复制标题
DOI：
10.1111/php.13305
复制
发表时间：
2020-11
影响因子：
3.3
通讯作者：
Ahmad N
中科院分区：
文献类型：
--
作者：
Garcia-Peterson LM;Ndiaye MA;Chhabra G;Singh CK;Guzmán-Pérez G;Iczkowski KA;Ahmad N
黑色素瘤是皮肤癌中最具侵袭性、潜在致命性的形式之一，并且已被证明与太阳紫外线辐射依赖性的起始和进展相关。尽管靶向和免疫治疗最近取得了显着进展，但持久和无复发生存仍然是重要的问题。因此，需要额外的新的机制为基础的方法，有效的黑色素瘤管理。沉默调节蛋白SIRT 6似乎在黑素细胞中具有促增殖功能。在这项研究中，我们确定了SIRT 6基因操作在人黑色素瘤细胞中的作用，在体外以及在体内。我们的数据表明，CRISPR/Cas9介导的A375黑色素瘤细胞中SIRT 6的敲除（KO）导致i）生长、活力、克隆形成存活率的显著降低，以及ii）G1期细胞周期停滞的诱导。此外，采用包含84个关键转化和肿瘤发生基因的RT 2 Profiler PCR阵列，我们发现SIRT 6 KO导致参与血管生成、凋亡、细胞衰老、上皮向间质转化、缺氧信号传导和端粒维持的基因的调节。最后，我们发现SIRT 6 KO A375细胞在无胸腺裸小鼠中的致瘤性显着降低。我们的数据提供了强有力的证据表明，SIRT 6促进黑色素瘤细胞的存活，无论是在体外还是在体内，并可以作为黑色素瘤管理的目标。SIRT 6已被证明是一种肿瘤促进剂或抑制剂，这取决于癌症类型。这项研究支持SIRT 6在黑色素瘤中的肿瘤促进作用，黑色素瘤是紫外线相关皮肤癌中最致命的形式之一。我们发现CRISPR/Cas9介导的SIRT 6敲除（KO）在体外赋予人黑素瘤细胞显著的抗增殖作用和体内抗肿瘤反应。此外，我们发现SIRT 6 KO显著影响几种癌症相关途径，包括细胞凋亡，细胞衰老和上皮-间质转化，表明SIRT 6在黑色素瘤进展中具有重要作用。因此，SIRT 6抑制方法可能用于黑色素瘤管理，并应进一步探索。
Melanoma is one of the most aggressive, potentially fatal forms of skin cancer, and has been shown to be associated with solar ultraviolet radiation-dependent initiation and progression. Despite remarkable recent advances with targeted- and immune- therapeutics, lasting and recurrence-free survival remain significant concerns. Therefore, additional novel mechanism-based approaches are needed for effective melanoma management. The sirtuin SIRT6 appears to have a pro-proliferative function in melanocytic cells. In this study, we determined the effects of genetic manipulation of SIRT6 in human melanoma cells, in vitro as well as in vivo. Our data demonstrated that CRISPR/Cas9-mediated knockout (KO) of SIRT6 in A375 melanoma cells resulted in a significant i) decrease in growth, viability, clonogenic survival, and ii) induction of G1-phase cell cycle arrest. Further, employing a RT2 Profiler PCR array containing 84 key transformation and tumorigenesis genes, we found that SIRT6 KO resulted in modulation of genes involved in angiogenesis, apoptosis, cellular senescence, epithelial-to-mesenchymal transition, hypoxia signaling, and telomere maintenance. Finally, we found significantly decreased tumorigenicity of SIRT6 KO A375 cells in athymic nude mice. Our data provide strong evidence that SIRT6 promotes melanoma cell survival, both in vitro and in vivo, and could be exploited as a target for melanoma management. SIRT6 has been shown to act as a tumor promoter or suppressor depending on the cancer type. This study supports the tumor promoter role of SIRT6 in melanoma, one of the deadliest forms of UV-related skin cancers. We found CRISPR/Cas9-mediated SIRT6 knockout (KO) imparted marked anti-proliferative effects in human melanoma cells in vitro and anti-tumorigenic response in vivo. Additionally, we found SIRT6 KO significantly affected several cancer-associated pathways, including apoptosis, cellular senescence, and epithelial-to-mesenchymal transition, suggesting SIRT6 has an important role in melanoma progression. Thus, SIRT6 inhibitory approaches could potentially be used in melanoma management and should be explored further.
登录
查看更多内容
影响因子：
13.8
作者：
Kugel, Site;Mostoslavsky, Raul
通讯作者：
Mostoslavsky, Raul
影响因子：
10.5
作者：
Ohanna, Mickael;Giuliano, Sandy;Bertolotto, Corine
通讯作者：
Bertolotto, Corine
胰岛素样生长因子结合蛋白 5 (IGFBP5) 在人类黑色素瘤细胞中发挥肿瘤抑制因子的作用
影响因子：
--
作者：
Wang J;Ding N;Li Y;Cheng H;Wang D;Yang Q;Deng Y;Yang Y;Li Y;Ruan X;Xie F;Zhao H;Fang X
通讯作者：
Fang X
Sirtuin 6 通过灭活 TGF-β 1/Smad3 信号传导抑制特发性肺纤维化过程中上皮细胞向间质细胞的转变
影响因子：
--
作者：
Tian, Kunming;Chen, Panpan;Zhou, Xue
通讯作者：
Zhou, Xue
影响因子：
11.5
作者：
Chen, Peiwen;Huang, Yujie;Luo, Yongzhang
通讯作者：
Luo, Yongzhang