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 .

The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review

“…This progressive increase in DNA methylation seen in vitro is comparable to the observations in CIN and cervical cancer tissues, also demonstrating a gradual increase in methylation with progression to cancer (see Figure 1). 11 The functional relevance of methylation‐mediated gene silencing during HPV‐induced carcinogenesis has been demonstrated for a subset of currently known methylation targets, including miR124‐2 , CADM1 , MAL and PAX1 12–19 …”

Cervical cancer risk profiling: molecular biomarkers predicting the outcome of hrHPV infection

“…Moreover, combined parallel testing of Pap smears and PAX1 m level gave better specificity (84% vs. 66%; p < 0.0001 by chi-square test) and equivalent sensitivity (93% vs. 97%; p = 0.2450 by chi-square test) to the combination of Pap smears and hrHPV DNA testing [160]. These findings led to the approval by the Taiwanese FDA of PAX1 methylation testing as an adjunct to cytology for cervical cancer screening in 2016 [98,161].…”

Methylated Septin9: biomarker for diagnosis of cervical cancer in cervical scrapings and for prediction of pelvic lymphatic metastasis in plasma

“…Many genes, including PAX1, SOX1, PCDHA, DCC, EPB41L3, and FAM19A4, have been confirmed to be hypermethylated in cervical scrapings diagnosed as CINⅡ or other aforementioned lesions (≥ CINⅡ) [3][4][5][6]. PAX1 methylation also as an adjunct screening method for cervical cancer has been approved by Taiwan FDA [7], laying the foundation for the future application of more biomarkers to the diagnosis of carcinoma.…”