The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC
The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC
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DOI：
10.1158/2159-8290.cd-18-1261
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发表时间：
2019-11-01
期刊：
影响因子：
28.2
通讯作者：
Shaw, Reuben J.
中科院分区：
文献类型：
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作者：
Hollstein, Pablo E.;Eichner, Lillian J.;Shaw, Reuben J.
LKB1（也称为STK11）肿瘤抑制基因突变是非小细胞肺癌（NSCLC）中第三常见的基因改变。LKB1编码一种丝氨酸/苏氨酸激酶，该激酶直接磷酸化并激活14种AMPK家族激酶（“AMPKRs”）。许多AMPKRs的功能尚不清楚，其中对LKB1的肿瘤抑制功能最关键的AMPKRs仍不清楚。在这里，我们将CRISPR和NSCLC细胞系和小鼠模型中的AMPKR家族的遗传分析结合起来，揭示了SIK亚家族令人惊讶的关键作用。Sik1的条件性遗传缺失显示kras依赖性肺癌小鼠模型中肿瘤生长增加，相关激酶Sik3的缺失进一步增强了肿瘤生长。由于大多数已知的SIKs底物控制转录，因此进行了基因表达分析，揭示了LKB1-和sik1 /3缺陷肿瘤中AP1和IL6信号的上调。SIK底物CRTC2是实现这种效果以及SIK损失带来的增殖益处所必需的。意义：肿瘤抑制因子LKB1/STK11编码一种在非小细胞肺癌中经常失活的丝氨酸/苏氨酸激酶。LKB1激活AMPK家族中控制生长和代谢的14个下游激酶，尽管哪些激酶对LKB1肿瘤抑制功能至关重要仍然是一个谜。在这里，我们意外地发现两个未被充分研究的激酶，SIK1和SIK3，是肺癌的关键靶点。
Mutations in the LKB1 (also known as STK11) tumor suppressor are the third most frequent genetic alteration in non-small cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras-dependent lung cancer, which was further enhanced by loss of the related kinase Sik3. As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss.SIGNIFICANCE: The tumor suppressor LKB1/STK11 encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer.