...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>EBioMedicine >Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma
【24h】

Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma

机译：CRL4-CDT2-SET8 / p21泛素化和降解轴的失活奠定了pevonedistat治疗黑色素瘤的疗效

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle ''rereplication'' through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. CDT2 ablation inhibited a panel of melanoma cell lines through the induction of SET8- and p21-dependent DNA rereplication and senescence. Pevonedistat (MLN4924), a specific inhibitor of the NEDD8 activating enzyme (NAE), inhibits the activity of cullin E3 ligases, thereby stabilizing a vast number of cullin substrates and resulting in cancer cell inhibition in vitro and tumor suppression in nude mice. We demonstrate that pevonedistat is effective at inhibiting the proliferation of melanoma cell lines in vitro through the induction of rereplication-dependent permanent growth arrest as well as through a transient, non-rereplication-dependent mechanism. CRISPR/Cas9-mediated heterozygous deletion of CDKN1A (encoding p21) or SET8 in melanoma cells demonstrated that the rereplication-mediated cytotoxicity of pevonedistat is mediated through preventing the degradation of p21 and SET8 and is essential for melanoma suppression in nude mice. By contrast, pevonedistat-induced transient growth suppression was independent of p21 or SET8, and insufficient to inhibit tumor growth in vivo. Pevonedistat additionally synergized with the BRAF kinase inhibitor PLX4720 to inhibit BRAF melanoma, and suppressed PLX4720-resistant melanoma cells. These findings demonstrate that the CRL4-CDT2-SET8/p21 degradation axis is the primary target of inhibition by pevonedistat in melanoma and suggest that a broad patient population may benefit from pevonedistat therapy. Research in Context: The identification of new molecular targets and effective inhibitors is of utmost significance for the clinical management of melanoma. This study identifies CDT2, a substrate receptor for the CRL4 ubiquitin ligase, as a prognostic marker and therapeutic target in melanoma. CDT2 is required for melanoma cell proliferation and inhibition of CRL4^C^D^T^2 by pevonedistat suppresses melanoma in vitro and in vivo through the induction of DNA rereplication and senescence through the stabilization of the CRL4^C^D^T^2 substrates p21 and SET8. Pevonedistat also synergizes with vemurafenib in vivo and suppresses vemurafenib-resistant melanoma cells. These findings show a significant promise for targeting CRL4^C^D^T^2 therapeutically.
机译：基于cullin的CRL4-CDT2泛素连接酶正在成为细胞增殖的主要调节剂。 CRL4-CDT2通过在细胞周期S期靶向降解CDT1，SET8和p21，防止在同一细胞周期``复制''过程中DNA复制的重新启动。我们显示CDT2在皮肤黑色素瘤中过表达，并预测整体和无病生存期较差。 CDT2切除通过诱导SET8和p21依赖的DNA复制和衰老抑制了一组黑色素瘤细胞系。 Pevonedistat（MLN4924）是NEDD8活化酶（NAE）的特异性抑制剂，可抑制cullin E3连接酶的活性，从而稳定大量cullin底物并导致体外抑制癌细胞和抑制裸鼠体内的肿瘤。我们证明，pevonedistat可有效地通过诱导依赖复制的永久性生长停滞以及短暂的，非复制依赖性的机制，在体外抑制黑素瘤细胞系的增殖。 CRISPR / Cas9介导的黑色素瘤细胞中CDKN1A（编码p21）或SET8杂合缺失表明，pevonedistat的复制介导的细胞毒性是通过防止p21和SET8降解而介导的，对于抑制裸鼠中的黑色素瘤至关重要。相比之下，pevonedistat诱导的瞬时生长抑制独立于p21或SET8，不足以抑制体内肿瘤的生长。 Pevonedistat还可与BRAF激酶抑制剂PLX4720协同作用，以抑制BRAF黑色素瘤，并抑制PLX4720耐药的黑色素瘤细胞。这些发现表明，CRL4-CDT2-SET8 / p21降解轴是pevonedistat抑制黑素瘤的主要靶标，并表明广泛的患者人群可能会受益于pevonedistat治疗。背景研究：鉴定新的分子靶标和有效抑制剂对黑素瘤的临床治疗至关重要。这项研究确定CDT2是CRL4泛素连接酶的底物受体，它是黑色素瘤的预后标志物和治疗靶标。 CDT2是黑色素瘤细胞增殖所必需的，pevonedistat对CRL4 ^ C ^ D ^ T ^ 2的抑制通过诱导DNA复制和衰老通过稳定CRL4 ^ C ^ D ^ T ^ 2抑制了体内和体外的黑色素瘤。基板p21和SET8。 Pevonedistat还可在体内与vemurafenib协同作用并抑制对vemurafenib耐药的黑色素瘤细胞。这些发现显示出在治疗上靶向CRL4 ^ C ^ D ^ T ^ 2的重大前景。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号