The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma.
Hidenori MachinoSyuzo KanekoMasaaki KomatsuNoriko IkawaKen AsadaRyuichiro NakatoKanto ShozuAi DozenKenbun SoneHiroshi YoshidaTomoyasu KatoKatsutoshi OdaYutaka OsugaTomoyuki FujiiGottfried von KeudellVassiliki SalouraRyuji HamamotoPublished in: Communications biology (2022)
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.
Keyphrases
- cell cycle
- high grade
- cell proliferation
- poor prognosis
- rna seq
- low grade
- single cell
- long non coding rna
- genome wide
- signaling pathway
- pi k akt
- end stage renal disease
- chronic kidney disease
- stress induced
- dna damage
- vascular endothelial growth factor
- stem cells
- transcription factor
- prognostic factors
- oxidative stress
- protein kinase
- tyrosine kinase
- binding protein
- genome wide identification