AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer
AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer
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DOI：
10.1038/s41388-017-0054-6
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Hoepker, Katja
中科院分区：
文献类型：
--
作者：
Welcker, Daniela;Jain, Manaswita;Hoepker, Katja
恶性转化的一个基本原理是癌细胞能够逃避对DNA损伤的自然发生的细胞内反应。尽管DNA损伤累积，肿瘤仍会进展。然而，这种耐受遗传毒性应激的潜在机制仍然很差的特点。在这里，我们表明，复制压力发生在Kras驱动的小鼠肺腺癌，以及在增殖的小鼠胚胎和成人组织。我们确定了转录调节因子AATF/CHE-1作为一个关键分子，通过抑制体内p53驱动的凋亡来维持增殖组织和肿瘤进展。在本地Kras驱动的肺腺癌模型中，Aatf的缺失主要以p53依赖的方式延迟肺癌形成。此外，通过双重重组酶策略靶向现有肿瘤中的Aatf导致肿瘤进展停止。总之，这些数据表明，AATF可以作为治疗KRAS驱动的恶性肿瘤的药物靶标。
A fundamental principle in malignant tranformation is the ability of cancer cells to escape the naturally occurring cellintrinsic responses to DNA damage. Tumors progress despite the accumulation of DNA lesions. However, the underlying mechanisms of this tolerance to genotoxic stress are still poorly characterized. Here, we show that replication stress occurs in Kras-driven murine lung adenocarcinomas, as well as in proliferating murine embryonic and adult tissues. We identify the transcriptional regulator AATF/CHE-1 as a key molecule to sustain proliferative tissues and tumor progression in parts by inhibiting p53-driven apoptosis in vivo. In an autochthonous Kras-driven lung adenocarcinoma model, deletion of Aatf delayed lung cancer formation predominantly in a p53-dependent manner. Moreover, targeting Aatf in existing tumors through a dual recombinase strategy caused a halt in tumor progression. Taken together, these data suggest that AATF may serve as a drug target to treat KRAS-driven malignancies.