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

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

doi:10.1038/s42003-021-02992-4

Cited by 17 publications

(21 citation statements)

References 51 publications

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“…Similarly, when MARK3 knockout is combined with GGTI-298, the effect on transcription of YAP1/TAZ target genes is significantly enhanced, and the growth of some MARK3 KO UM cell lines is synergistically inhibited. However, the synergistic effect of the combination is not expression significantly correlated with poor prognosis in HGSOC patients [39]. This report is in contrast with our finding that high levels of MARK3 correlates with worse prognosis of UM patients and that higher MARK3 expression correlated with monosomy of chromosome 3.…”

Section: Discussioncontrasting

confidence: 99%

Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines

Glinkina,

Prieto,

Teunisse

et al. 2023

Preprint

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Uveal melanoma (UM) is an ocular tumor that often develops asymptomatically. Statistically, every second patient eventually develops metastases that drastically worsen the prognosis by several months of overall survival. While isolated liver perfusion with melphalan and more recently immunotherapy (Tebentafusp) are the few treatment options available for metastatic UM patients, their application is complex or expensive. There is an urgent need to understand drug response and identify potential avenues for therapy. Hence, we focused on uncovering altered phosphorylation signaling events in metastatic UM using proteomics as an approach to identify potential drug targets.We analyzed the phosphoproteomes of the primary UM cell line Mel270 and two cell lines OMM2.3 and OMM2.5, derived from metastatic lesions of the same patient. We found 177 phosphosites to be altered significantly between primary and metastatic cell lines. Pathway analysis of up-regulated phosphosites in metastatic lines suggests that Rho signaling and mitotic cell cycle to be significantly altered uncovering potential routes of signaling for metastasis. Clinical data from LUMC and TCGA datasets uncoveredMARK3expression (which links to Rho signaling) correlation with chromosome 3 status, a prognostic marker in UM, suggesting that MARK3 kinase might be involved in metastatic UM signaling.

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Section: Discussioncontrasting

confidence: 99%

Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines

Glinkina,

Prieto,

Teunisse

et al. 2023

Preprint

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“…While prior studies have identified functions for specific MARK kinases in cancer (32)(33)(34), the essential redundant function of MARK2/3 in human cancer cells has, to our knowledge, not been previously defined.…”

Section: Resultsmentioning

confidence: 91%

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer

Klingbeil,

Skopelitis,

Tonelli

et al. 2024

Preprint

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The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein fromH. pylorias a catalytic inhibitor of MARK2/3, which we show exerts anti-tumor activityin vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.

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“…After 48 h, cells were washed with ice-cold PBS (−), and total RNA was extracted using QIAzol Lysis Reagent and RNeasy Plus Mini Kit (Qiagen; 73404), according to the manufacturer’s instructions. The subsequent steps have been previously described [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…Bioinformatic analysis of RNA-seq and ChIP-seq experiments were previously described [ 30 , 31 ]. Gene Ontology and pathway analyses were performed using the clusterProfiler R package (v3.14.3) and visualized using Cytoscape (v3.6.1) with plug-in (ClueGOv2.5.1) [ 32 , 33 , 34 ].…”

Section: Methodsmentioning

confidence: 99%

The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells

Kukita

Sone

Kaneko

et al. 2022

Cancers

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The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

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

Cited by 17 publications

References 51 publications

Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines

Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer

The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells

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