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

Lookup NU author(s): Dr Wei-Yu Lin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019, The Author(s). 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.


Publication metadata

Author(s): Su P-H, Lai H-C, Huang R-L, Chen L-Y, Wang Y-C, Wu T-I, Chan MWY, Liao C-C, Chen CW, Lin W-Y, Chang C-C

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 24/06/2019

Acceptance date: 07/06/2019

Date deposited: 08/07/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-019-45477-5

DOI: 10.1038/s41598-019-45477-5


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