Hypermethylation of LATS2 Promoter and Its Prognostic Value in IDH-Mutated Low-Grade Gliomas.

Yuan Gu,Yu Wang,Wei Hua,Ying Liu,Mingyue Ma,Jiaqian Luo,Fa-Xing Yu,Yebin Wang,Xin Wang

doi:10.3389/fcell.2020.586581

Yuan Gu, Yu Wang + Show 7 more

Open Access

https://doi.org/10.3389/fcell.2020.586581

Copy DOI

Abstract

Mutations in the enzyme isocitrate dehydrogenase 1/2 (IDH1/2) are the most common somatic mutations in low-grade glioma (LGG). The Hippo signaling pathway is known to play a key role in organ size control, and its dysregulation is involved in the development of diverse cancers. Large tumor suppressor 1/2 (LATS1/2) are core Hippo pathway components that phosphorylate and inactivate Yes-associated protein (YAP), a transcriptional co-activator that regulates expression of genes involved in tumorigenesis. A recent report from The Cancer Genome Atlas (TCGA) has highlighted a frequent hypermethylation of LATS2 in IDH-mutant LGG. However, it is unclear if LATS2 hypermethylation is associated with YAP activation and prognosis of LGG patients. Here, we performed a network analysis of the status of the Hippo pathway in IDH-mutant LGG samples and determined its association with cancer prognosis. Combining TCGA data with our biochemical assays, we found hypermethylation of LATS2 promoter in IDH-mutant LGG. LATS2 hypermethylation, however, did not translate into YAP activation but highly correlated with IDH mutation. LATS2 hypermethylation may thus serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.

Highlights

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), mainly Arg132 for IDH1 and Arg140 and Arg172 for IDH2, occur in over 80% of low-grade glioma (LGG) (Parsons et al, 2008; Watanabe et al, 2009; Yang et al, 2012; Cancer Genome Atlas Research Network et al, 2015; Suzuki et al, 2015)
We examined LATS2 methylation level and mRNA expression in LGG dataset from The Cancer Genome Atlas (TCGA), and found that LATS2 promoter was hypermethylated and LATS2 mRNA was repressed in IDHmutant LGG compared to IDH-wild type LGG (Figures 1A,B)
It is worth noting that while LATS2 promoter hypermethylation had been reported in another cancer with frequent IDH mutations, namely IDHmutant acute myeloid leukemia (AML), it did not downregulate LATS2 expression as it did in LGG (Supplementary Figure 1A), suggesting a different mechanism or role

Summary

Introduction

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), mainly Arg132 for IDH1 and Arg140 and Arg172 for IDH2, occur in over 80% of low-grade glioma (LGG) (Parsons et al, 2008; Watanabe et al, 2009; Yang et al, 2012; Cancer Genome Atlas Research Network et al, 2015; Suzuki et al, 2015). While wild type IDH1/2 converts isocitrate to α-ketoglutarate (αKG), gainof-function mutations of IDH1/2 lead to the production and accumulation of oncometabolite R-2-hydroxyglutarate (R-2HG) (Zhao et al, 2009; Ward et al, 2010). LATS1/2, in turn, phosphorylate and inactivate Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1(WWTR1, known as TAZ), which function as transcription co-activators and serve as Hippo pathway downstream effectors by regulating expression of genes involved in cell proliferation, death, and differentiation. LATS2 deficiency, for instance, has been studied in several cancers including glioma (Kawahara et al, 2008; Guo et al, 2017, 2019; Ye et al, 2017; Jin et al, 2018; Pan et al, 2018; Shi et al, 2018, 2019; He et al, 2019; Hsu et al, 2019)

Methods

Results

Conclusion