PHLPP2 is a novel biomarker and epigenetic target for the treatment of vitamin C in pancreatic cancer

Chen,Lin; Song,Huan; Luo,Zhongguang; Cui,Haoshu; Zheng,Wanwei; Liu,Yao; Li,Wenshuai; Luo,Feifei; Liu,Jie

doi:10.3892/ijo.2020.5001

PHLPP2 is a novel biomarker and epigenetic target for the treatment of vitamin C in pancreatic cancer

Authors:
- Lin Chen
- Huan Song
- Zhongguang Luo
- Haoshu Cui
- Wanwei Zheng
- Yao Liu
- Wenshuai Li
- Feifei Luo
- Jie Liu
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Affiliations: Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, P.R. China
Published online on: February 25, 2020 https://doi.org/10.3892/ijo.2020.5001
Pages: 1294-1303

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Abstract

Epigenetic dysregulations are closely associated with the development of pancreatic ductal adenocarcinoma (PDAC), which is one of the most aggressive malignancies and currently has limited treatment options. Vitamin C (VC), an epigenetic mediator, exerts antitumor effects on several types of cancer. However, the clinical application of VC is limited, particularly in PDAC. Thus, to investigate the antitumor effects and explore the potential clinical application of VC in PDAC, the survival of patients from The Cancer Genome Atlas database were analyzed, and proliferation, apoptosis and migration assays were performed in the present study. It was first established that high expression levels of the sodium‑dependent VC transporter 2, a critical VC transporter, predicted a good prognosis in patients with pancreatic adenocarcinoma. It was further confirmed that VC directly inhibited proliferation, induced apoptosis and suppressed migration of human pancreatic cancer cells. Global 5‑hydroxymethylcytosine (5hmC) content was significantly upregulated in pancreatic cancer cells following VC treatment, predominantly relying on ten‑eleven translocation 2. Furthermore, VC could specifically increase 5hmC levels at the promotor region on PH domain leucine‑rich repeat protein phosphatase 2 (PHLPP2) and enhance PHLPP2 expression levels. When PHLPP2 expression levels were knocked down, VC was able to partially overcome the inhibition of pancreatic cancer cells. These results illustrated a novel and precise mechanism of action of epigenetic alterations that underly the inhibition of VC in pancreatic cancer, and emphasized that PHLPP2 may be a new biomarker and epigenetic target for the clinical treatment of VC in PDAC.

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