Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer

Po Hsuan Su, Hung Cheng Lai, Rui Lan Huang, Lin Yu Chen, Yu Chi Wang, Tzu I. Wu, Michael W.Y. Chan, Chi Chun Liao, Chien Wen Chen, Wei Yu Lin, Cheng Chang Chang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

DNA methylation alteration, such as global hypomethylation and localized hypermethylation, within the promoters of tumor suppressor genes, is an important risk factor in cervical cancer. The potential use of DNA methylation detection, in cervical cancer screening or triage of mildly abnormal cytology, has recently been demonstrated. In particular, PAX1 DNA methylation testing was approved as an adjunct to cytology, in Taiwan, and is now undergoing registration trials in China. However, the function of PAX1 in cancer biology remains largely unknown. Here, we show that PAX1 inhibits malignant phenotypes upon oncogenic stress. Specifically, PAX1 expression inhibited the phosphorylation of multiple kinases, after challenges with oncogenic growth factors such as EGF and IL-6. Analogously, PAX1 activated a panel of phosphatases, including DUSP1, 5, and 6, and inhibited EGF/MAPK signaling. PAX1 also interacted with SET1B, increasing histone H3K4 methylation and DNA demethylation of numerous phosphatase-encoding genes. Furthermore, hypermethylated PAX1 associated with poor prognosis in cervical cancer. Taken together, this study reveals, for the first time, the functional relevance of PAX1 in cancer biology, and further supports the prospect of targeting multifold oncogenic kinase cascades, which jointly contribute to multiresistance, via epigenetic reactivation of PAX1.

Original languageEnglish
Article number9195
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

DNA Methylation
Phosphoric Monoester Hydrolases
Uterine Cervical Neoplasms
Phosphotransferases
Epidermal Growth Factor
Cell Biology
Triage
Tumor Suppressor Genes
Taiwan
Early Detection of Cancer
Epigenomics
Histones
Interleukin-6
China
Neoplasms
Intercellular Signaling Peptides and Proteins
Phosphorylation
Phenotype
Genes

ASJC Scopus subject areas

  • General

Cite this

Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer. / Su, Po Hsuan; Lai, Hung Cheng; Huang, Rui Lan; Chen, Lin Yu; Wang, Yu Chi; Wu, Tzu I.; Chan, Michael W.Y.; Liao, Chi Chun; Chen, Chien Wen; Lin, Wei Yu; Chang, Cheng Chang.

In: Scientific Reports, Vol. 9, No. 1, 9195, 01.12.2019.

Research output: Contribution to journalArticle

@article{06f00c5041b04b2f9a3757c33b7a2ebe,
title = "Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer",
abstract = "DNA methylation alteration, such as global hypomethylation and localized hypermethylation, within the promoters of tumor suppressor genes, is an important risk factor in cervical cancer. The potential use of DNA methylation detection, in cervical cancer screening or triage of mildly abnormal cytology, has recently been demonstrated. In particular, PAX1 DNA methylation testing was approved as an adjunct to cytology, in Taiwan, and is now undergoing registration trials in China. However, the function of PAX1 in cancer biology remains largely unknown. Here, we show that PAX1 inhibits malignant phenotypes upon oncogenic stress. Specifically, PAX1 expression inhibited the phosphorylation of multiple kinases, after challenges with oncogenic growth factors such as EGF and IL-6. Analogously, PAX1 activated a panel of phosphatases, including DUSP1, 5, and 6, and inhibited EGF/MAPK signaling. PAX1 also interacted with SET1B, increasing histone H3K4 methylation and DNA demethylation of numerous phosphatase-encoding genes. Furthermore, hypermethylated PAX1 associated with poor prognosis in cervical cancer. Taken together, this study reveals, for the first time, the functional relevance of PAX1 in cancer biology, and further supports the prospect of targeting multifold oncogenic kinase cascades, which jointly contribute to multiresistance, via epigenetic reactivation of PAX1.",
author = "Su, {Po Hsuan} and Lai, {Hung Cheng} and Huang, {Rui Lan} and Chen, {Lin Yu} and Wang, {Yu Chi} and Wu, {Tzu I.} and Chan, {Michael W.Y.} and Liao, {Chi Chun} and Chen, {Chien Wen} and Lin, {Wei Yu} and Chang, {Cheng Chang}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-45477-5",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Paired Box-1 (PAX1) Activates Multiple Phosphatases and Inhibits Kinase Cascades in Cervical Cancer

AU - Su, Po Hsuan

AU - Lai, Hung Cheng

AU - Huang, Rui Lan

AU - Chen, Lin Yu

AU - Wang, Yu Chi

AU - Wu, Tzu I.

AU - Chan, Michael W.Y.

AU - Liao, Chi Chun

AU - Chen, Chien Wen

AU - Lin, Wei Yu

AU - Chang, Cheng Chang

PY - 2019/12/1

Y1 - 2019/12/1

N2 - DNA methylation alteration, such as global hypomethylation and localized hypermethylation, within the promoters of tumor suppressor genes, is an important risk factor in cervical cancer. The potential use of DNA methylation detection, in cervical cancer screening or triage of mildly abnormal cytology, has recently been demonstrated. In particular, PAX1 DNA methylation testing was approved as an adjunct to cytology, in Taiwan, and is now undergoing registration trials in China. However, the function of PAX1 in cancer biology remains largely unknown. Here, we show that PAX1 inhibits malignant phenotypes upon oncogenic stress. Specifically, PAX1 expression inhibited the phosphorylation of multiple kinases, after challenges with oncogenic growth factors such as EGF and IL-6. Analogously, PAX1 activated a panel of phosphatases, including DUSP1, 5, and 6, and inhibited EGF/MAPK signaling. PAX1 also interacted with SET1B, increasing histone H3K4 methylation and DNA demethylation of numerous phosphatase-encoding genes. Furthermore, hypermethylated PAX1 associated with poor prognosis in cervical cancer. Taken together, this study reveals, for the first time, the functional relevance of PAX1 in cancer biology, and further supports the prospect of targeting multifold oncogenic kinase cascades, which jointly contribute to multiresistance, via epigenetic reactivation of PAX1.

AB - DNA methylation alteration, such as global hypomethylation and localized hypermethylation, within the promoters of tumor suppressor genes, is an important risk factor in cervical cancer. The potential use of DNA methylation detection, in cervical cancer screening or triage of mildly abnormal cytology, has recently been demonstrated. In particular, PAX1 DNA methylation testing was approved as an adjunct to cytology, in Taiwan, and is now undergoing registration trials in China. However, the function of PAX1 in cancer biology remains largely unknown. Here, we show that PAX1 inhibits malignant phenotypes upon oncogenic stress. Specifically, PAX1 expression inhibited the phosphorylation of multiple kinases, after challenges with oncogenic growth factors such as EGF and IL-6. Analogously, PAX1 activated a panel of phosphatases, including DUSP1, 5, and 6, and inhibited EGF/MAPK signaling. PAX1 also interacted with SET1B, increasing histone H3K4 methylation and DNA demethylation of numerous phosphatase-encoding genes. Furthermore, hypermethylated PAX1 associated with poor prognosis in cervical cancer. Taken together, this study reveals, for the first time, the functional relevance of PAX1 in cancer biology, and further supports the prospect of targeting multifold oncogenic kinase cascades, which jointly contribute to multiresistance, via epigenetic reactivation of PAX1.

UR - http://www.scopus.com/inward/record.url?scp=85067882683&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067882683&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-45477-5

DO - 10.1038/s41598-019-45477-5

M3 - Article

C2 - 31235851

AN - SCOPUS:85067882683

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 9195

ER -