Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling
Novel CDK9 inhibitor oroxylin A promotes wild-type P53 stability and prevents hepatocellular carcinoma progression by disrupting both MDM2 and SIRT1 signaling
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新型 CDK9 抑制剂 oroxylin A 通过破坏 MDM2 和 SIRT1 信号传导促进野生型 P53 稳定性并预防肝细胞癌进展
DOI：
10.1038/s41401-021-00708-2
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发表时间：
2021-06
影响因子：
8.2
通讯作者：
Libin Wei
中科院分区：
文献类型：
--
作者：
Jingyue Yao;Shu Xu;Yue-Ning Sun;Ye Xu;Qinglong Guo;Libin Wei
肝细胞癌（HCC）是全球最致命的肿瘤之一。然而，由于HCC病因的高度异质性特点，一线索拉非尼治疗晚期HCC的效果未能延长患者的生存期。细胞周期蛋白依赖性激酶9（CDK9）是癌症治疗不断发展的重要靶点。在此，我们证明CDK9与HCC的进展密切相关，可以通过调节HCC的恢复来作为HCC治疗靶点。我们证明小鼠双分钟 2 同源物 (MDM2) 和 Sirtuin 1 (SIRT1) 分别在 Ser166 和 Ser47 处被 CDK9 磷酸化。抑制 CDK9 不仅可以减少 MDM2 介导的 wt-p53 泛素化和降解，还可以通过抑制 wt-p53 的脱乙酰酶活性来增加 wt-p53 的稳定性。 SIRT1。因此，抑制CDK9可促进wt-p53稳定并阻止HCC进展。然而，高浓度特异性CDK9抑制剂的过度抑制会抵消p53稳定性的促进作用，并由于极端的一般转录抑制而降低其抗HCC活性。探索了来自黄芩的新型CDK9抑制剂Oroxylin A（OA）的作用，结果表明OA对p53稳定性表现出中等和受控的抑制作用。 CDK9 活性和表达，并通过抑制 CDK9 调节的 MDM2 和 SIRT1 信号传导来稳定 wt-p53。这些结果表明 OA 对 HCC 的高治疗潜力及其在正常组织中的低毒性。这项研究证明了 CDK9 调节 wt-p53 的新机制，并表明 OA 是 HCC 治疗的潜在候选者。
Hepatocellular carcinoma (HCC) is one of the most lethal tumours worldwide.However,the effects of first-line sorafenib treatment in advanced HCC fail to prolong patients' survival due to the highly heterogeneous characteristics of HCC etiology.Cyclin-dependent kinase 9 (CDK9) is an important target in the continuous development of cancer therapy.Here,we demonstrate that CDK9 is closely associated with the progression of HCC and can serve as an HCC therapeutic target by modulating the recovery of wild-type p53 (wt-p53) function.We prove that mouse double minute 2 homologue (MDM2) and Sirtuin 1 (SIRT1) are phosphorylated by CDK9 at Ser166 and Ser47,respectively.Inhibition of CDK9 not only reduces the MDM2-mediated ubiquitination and degradation of wt-p53 but also increases wt-p53 stability by suppressing deacetylase activity of SIRT1.Thus,inhibition of CDK9 promotes the wt-p53 stabilization and prevents HCC progression.However,excessive inhibition by high concentrations of specific CDK9 inhibitors counteracts the promotion of p53 stability and reduces their anti-HCC activity because of extreme general transcription repression.The effects of a novel CDK9 inhibitor named oroxylin A (OA) from Scutellaria baicalensis are explored,with the results indicating that OA shows moderate and controlled inhibition of CDK9 activity and expression,and stabilizes wt-p53 by inhibiting CDK9-regulated MDM2 and SIRT1 signaling.These outcomes indicate the high therapeutic potential of OA against HCC and its low toxicity in normal tissue.This study demonstrates a novel mechanism for the regulation of wt-p53 by CDK9 and indicates that OA is a potential candidate for HCC therapy.
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影响因子：
7.3
作者：
Sonawane YA;Taylor MA;Napoleon JV;Rana S;Contreras JI;Natarajan A
通讯作者：
Natarajan A
影响因子：
64.5
作者：
Zhang H;Pandey S;Travers M;Sun H;Morton G;Madzo J;Chung W;Khowsathit J;Perez-Leal O;Barrero CA;Merali C;Okamoto Y;Sato T;Pan J;Garriga J;Bhanu NV;Simithy J;Patel B;Huang J;Raynal NJ;Garcia BA;Jacobson MA;Kadoch C;Merali S;Zhang Y;Childers W;Abou-Gharbia M;Karanicolas J;Baylin SB;Zahnow CA;Jelinek J;Graña X;Issa JJ
通讯作者：
Issa JJ
未折叠蛋白反应的激活导致了 oroxylin A 在人肝细胞癌 HepG2 细胞中的选择性细胞毒性。
影响因子：
3.5
作者：
Xu, Min;Lu, Na;Sun, Zhongying;Zhang, Haiwei;Dai, Qinsheng;Wei, Libin;Li, Zhiyu;You, Qidong;Guo, Qinglong
通讯作者：
Guo, Qinglong
肝癌的发生需要通过 CD44 增强的生长因子信号传导抑制 p53
影响因子：
50.3
作者：
Dhar D;Antonucci L;Nakagawa H;Kim JY;Glitzner E;Caruso S;Shalapour S;Yang L;Valasek MA;Lee S;Minnich K;Seki E;Tuckermann J;Sibilia M;Zucman-Rossi J;Karin M
通讯作者：
Karin M
影响因子：
14.8
作者：
Olson CM;Jiang B;Erb MA;Liang Y;Doctor ZM;Zhang Z;Zhang T;Kwiatkowski N;Boukhali M;Green JL;Haas W;Nomanbhoy T;Fischer ES;Young RA;Bradner JE;Winter GE;Gray NS
通讯作者：
Gray NS