RRC ID 69159
著者 Machino H, Kaneko S, Komatsu M, Ikawa N, Asada K, Nakato R, Shozu K, Dozen A, Sone K, Yoshida H, Kato T, Oda K, Osuga Y, Fujii T, von Keudell G, Saloura V, Hamamoto R.
タイトル The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma.
ジャーナル Commun Biol
Abstract High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. However, it is still unclear how genetic dysregulations and biological processes generate the malignant subtype of HGSOC. Here we show that expression levels of microtubule affinity-regulating kinase 3 (MARK3) are downregulated in HGSOC, and that its downregulation significantly correlates with poor prognosis in HGSOC patients. MARK3 overexpression suppresses cell proliferation and angiogenesis of ovarian cancer cells. The LKB1-MARK3 axis is activated by metabolic stress, which leads to the phosphorylation of CDC25B and CDC25C, followed by induction of G2/M phase arrest. RNA-seq and ATAC-seq analyses indicate that MARK3 attenuates cell cycle progression and angiogenesis partly through downregulation of AP-1 and Hippo signaling target genes. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs.
巻・号 5(1)
ページ 39
公開日 2022-1-11
DOI 10.1038/s42003-021-02992-4
PII 10.1038/s42003-021-02992-4
PMID 35017636
PMC PMC8752757
MeSH AMP-Activated Protein Kinase Kinases / genetics* Biomarkers, Tumor / genetics Cell Line, Tumor Cell Proliferation / genetics Down-Regulation / genetics Epigenesis, Genetic / genetics Female Genes, Tumor Suppressor* Humans Ovarian Neoplasms* / genetics Ovarian Neoplasms* / pathology Protein Serine-Threonine Kinases / genetics* Stress, Physiological / genetics*
IF 4.165
リソース情報
ヒト・動物細胞 JHOS-2(RCB1521) JHOS-4(RCB1678) NIH:OVCAR-3(RCB2135)