CSK-homologous kinase (CHK/MATK) is a potential colorectal cancer tumour suppressor gene epigenetically silenced by promoter methylation

Chüeh, Anderly C.; Advani, Gahana; Foroutan, Momeneh; Smith, Jai; Ng, Nadia L.Y.; Nandurkar, Harshal; Lio, Daisy Sio Seng; Zhu, Hong; Chong, Yuh Ping; Verkade, Heather; Fujita, Daishi; Bjorge, Jeffrey D.; Basheer, Faiza; Lim, Jet Phey; Luk, Ian Y.; Dhillon, Amardeep S.; Sakthianandeswaren, Anuratha; Mouradov, Dmitri; Sieber, Oliver M.; Hollande, Frédéric; Mariadason, John M.; Cheng, Heung Chin

doi:10.1038/s41388-021-01755-z

Cited by 14 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the identification and analysis of methylationregulated differentially expressed genes (MeDEGs) will be of great significance. Most previous studies have demonstrated that methylation in the promoter region tends to inhibit gene expression, while hypomethylation promotes gene expression [19,21]. Here, we identified 1113 MeDEGs by analyzing gene expression profiling datasets (GSE69428, GSE18520, GSE54388, and GSE27651) and gene methylation profiling dataset (GSE133556) of HGSOC tissues extracted from the GEO database.…”

Section: Discussionmentioning

confidence: 99%

The Expression and Role Analysis of Methylation-Regulated Differentially Expressed Gene UBE2C in Pan-Cancer, Especially for HGSOC

Sun

Zhi

et al. 2022

Cancers

View full text Add to dashboard Cite

High-grade serous ovarian cancer (HGSOC) is the most fatal gynecological malignant tumor. DNA methylation is associated with the occurrence and development of a variety of tumor types, including HGSOC. However, the signatures regarding DNA methylation changes for HGSOC diagnosis and prognosis are less explored. Here, we screened differentially methylated genes and differentially expressed genes in HGSOC through the GEO database. We identified that UBE2C was hypomethylation and overexpression in ovarian cancer, which was associated with more advanced cancer stages and poor prognoses. Additionally, the pan-cancer analysis showed that UBE2C was overexpressed and hypomethylation in almost all cancer types and was related to poor prognoses for various cancers. Next, we established a risk or prognosis model related to UBE2C methylation sites and screened out the three sites (cg03969725, cg02838589, and cg00242976). Furthermore, we experimentally validated the overexpression of UBE2C in HGSOC clinical samples and ovarian cell lines using quantitative real-time PCR, Western blot, and immunohistochemistry. Importantly, we discovered that ovarian cancer cell lines had lower DNA methylation levels of UBE2C than IOSE-80 cells (normal ovarian epithelial cell line) by bisulfite sequencing PCR. Consistently, treatment with 5-Azacytidine (a methylation inhibitor) was able to restore the expression of UBE2C. Taken together, our study may help us to understand the underlying molecular mechanism of UBE2C in pan-cancer tumorigenesis; it may be a useful biomarker for diagnosis, treatment, and monitoring, not only of ovarian cancer but a variety of cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

The Expression and Role Analysis of Methylation-Regulated Differentially Expressed Gene UBE2C in Pan-Cancer, Especially for HGSOC

Sun

Zhi

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…The inhibition of Src requires the activity of the C-terminal Src kinase (CSK) [ 20 ] or CSK homolog kinase (Chk/MATK) [ 21 ], which phosphorylate Src at Tyr527. In addition, several phosphatases, such as phosphatase and tensin homolog (PTEN), have been shown to dephosphorylate Src at Tyr416 [ 22 , 23 ], a step required to complete the inactivation and intramolecular assembly of Src (Fig.…”

Section: Src Structure and Regulationmentioning

confidence: 99%

Src: coordinating metabolism in cancer

Pelaz

Tabernero

2022

Oncogene

View full text Add to dashboard Cite

Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.

show abstract

“…In colon cancer cells, the downregulation of CHK expression was associated with a high level of promoter methylation of CHK, which has been shown to be associated with enhanced levels of DNA methyltransferases (DNMTs). The hypermethylation of CHK promoters by DNMT promotes the oncogenic properties of colon cancer cells (Chüeh et al, 2021;Zhu et al, 2021).…”

Section: Regulation Of Chk Expressionmentioning

confidence: 99%

“…Moreover, potential substrates such as β-synuclein have been identified for CHK, specifically (Ia, et al, 2011). Expression of CHK has been shown to be regulated epigenetically recently (Chüeh et al, 2021;Zhu et al, 2021). However, the physiological and pathological roles of CHK as well as the regulation of CHK are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Regulation, targets and functions of CHK

Zhu

Sun

Guo³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Src family kinases (SFKs) play pivotal roles in multiple signaling pathways (Yeatman, 2004). SFK activity is inhibited by phosphorylation at its C-terminal tyrosine, by CSK (C-terminal Src kinase) and CHK (CSK-homologous kinase). CHK expression is restricted to normal hematopoietic cells, brain, and colon tissues. Downregulation of CHK in brain and colon tumors contributes to tumorigenicity in these tissues. CHK does not phosphorylate Src efficiently, however, in contrast to CSK, CHK inhibits Src kinase activity allosterically. Although the functions of CHK are still largely unknown, potential substrates of CHK including β-synuclein, α-tubulin, α-spectrin, 14-3-3, and Hsp90 have been identified. CHK is regulated epigenetically via promoter methylation. As the unknown roles of CHK are beginning to be revealed, current knowledge of regulation, molecular targets and functions of CHK is summarized, and important topics for future CHK research are discussed.

show abstract

CSK-homologous kinase (CHK/MATK) is a potential colorectal cancer tumour suppressor gene epigenetically silenced by promoter methylation

Cited by 14 publications

References 50 publications

The Expression and Role Analysis of Methylation-Regulated Differentially Expressed Gene UBE2C in Pan-Cancer, Especially for HGSOC

The Expression and Role Analysis of Methylation-Regulated Differentially Expressed Gene UBE2C in Pan-Cancer, Especially for HGSOC

Src: coordinating metabolism in cancer

Regulation, targets and functions of CHK

Contact Info

Product

Resources

About