The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

Hidenori Machino,Vassiliki Saloura,Gottfried Von Keudell,Yutaka Osuga,Ai Dozen,Tomoyasu Kato,Syuzo Kaneko,Kanto Shozu,Kenbun Sone,Ryuji Hamamoto,Katsutoshi Oda,Ryuichiro Nakato,Masaaki Komatsu,Ken Asada,Tomoyuki Fujii,Noriko Ikawa,Hiroshi Yoshida

doi:10.1038/s42003-021-02992-4

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.

Highlights

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths
To further validate our analyses, RNA-seq data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects were surveyed using GEPIA15, indicating that microtubule affinity-regulating kinase 3 (MARK3) and MAF were consistently downregulated in HGSOCs (Supplementary Fig. 1b, c)
Given that our analysis identified that downregulation of MARK3 is significantly associated with poor clinical outcomes (Fig. 1e) and platinumresistant status in patients with HGSOC (Fig. 1f), we hypothesized that MARK3 acts as a tumor suppressor gene and offers a promising therapeutic opportunity

Summary

Introduction

High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs. 1234567890():,; High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, often detected at a late clinical-stage due to its rapid dissemination and metastasis, causing ~70% of deaths from ovarian cancer[1]. Among HR-proficient types, CCNE1 amplification is the most frequently observed genomic alteration, which accelerates the G1/ S phase transition, and results in poor clinical outcomes[8] This indicates that cell cycle dysregulation is critical to developing HRproficient HGSOCs. it should be noted that forced entry into mitosis may result in hazardous consequences because cell cycle transition is rigidly controlled by cell cycle checkpoints. We hypothesize that there is a hidden molecular mechanism enabling

Methods

Results

Conclusion