Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation.
Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation.
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作者：
Zhou X;Li JW;Chen Z;Ni W;Li X;Yang R;Shen H;Liu J;DeMayo FJ;Lu J;Kaye FJ;Wu L
LKB 1肿瘤抑制因子功能丧失的肺癌是一种常见的侵袭性亚组，没有有效的治疗方法。LKB 1缺陷诱导cAMP/CREB介导的转录由一个家族的三个CREB调节的转录辅激活因子（CRTC 1 -3）的组成性激活。然而，CRTC激活在促进LKB 1-null癌症的侵袭性表型中的意义和机制仍然很差。在这里，我们观察到重叠的CRTC表达模式和轻微的生长表型的个别CRTC-knockout在肺癌，表明功能冗余的CRTC 1 -3。因此，我们设计了一个显性负突变体（dnCRTC），以阻止所有三个CRTC结合和共激活CREB。dnCRTC的表达有效地抑制了由LKB 1缺陷诱导的异常激活的cAMP/CREB介导的致癌转录程序，并特异性地阻断了人和小鼠LKB 1失活的肺癌的生长。总的来说，这项研究提供了直接的证据CRTC-CREB激活在促进LKB 1-null肺癌的恶性表型的重要作用，并提出CRTC-CREB相互作用界面作为一种新的治疗靶点。
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 human and murine 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.