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Dependency of LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
bioRxiv - Cancer Biology Pub Date : 2021-01-09 , DOI: 10.1101/2021.01.09.425982
Xin Zhou , Jennifer W. Li , Zirong Chen , Wei Ni , Xuehui Li , Rongqiang Yang , Huangxuan Shen , Jian Liu , Francesco J. DeMayo , Jianrong Lu , Frederic J. Kaye , Lizi Wu

Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.

中文翻译:

LKB1灭活的肺癌对CRTC-CREB异常激活的依赖性

具有LKB1肿瘤抑制功能丧失的肺癌是一种常见的积极亚型,没有有效的治疗方法。LKB1缺乏症由三个CREB调控的转录共激活因子(CRTC1-3)家族诱导cAMP / CREB介导的转录的组成性激活。但是,CRTC激活在促进LKB1无效癌症的侵袭性表型中的意义和机制仍然不明确。在这里,我们观察到了重叠的CRTC表达模式和单个CRTC基因敲除的轻度生长表型,提示了CRTC1-3的功能冗余。因此,我们设计了一个显性负突变体(dnCRTC),以阻止所有三个CRTC结合并共同激活CREB。dnCRTC的表达有效地抑制了由LKB1缺乏引起的cAMP / CREB介导的致癌转录程序的异常激活,并特异性阻断了LKB1灭活的肺癌的生长。总的来说,这项研究直接证明了CRTC-CREB激活在促进LKB1-null肺癌的恶性表型中的重要作用,并提出了CRTC-CREB相互作用界面作为一种新型治疗靶点。
更新日期:2021-01-10
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