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Hollstein, Pablo E; Eichner, Lillian J; Brun, Sonja N; Kamireddy, Anwesh; Svensson, Robert U; Vera, Liliana I; Ross, Debbie S; Rymoff, T J; Hutchins, Amanda; Galvez, Hector M; Williams, April E; Shokhirev, Maxim N; Screaton, Robert A; Berdeaux, Rebecca; Shaw, Reuben J
Cancer discovery, 11/2019, Letnik: 9, Številka: 11Journal Article
Mutations in the LKB1 (also known as ) tumor suppressor are the third most frequent genetic alteration in non-small cell lung cancer (NSCLC). 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 revealed increased tumor growth in mouse models of -dependent lung cancer, which was further enhanced by loss of the related kinase . 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 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. .
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Vir: Osebne bibliografije
in: SICRIS
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