Research Papers:

The transcription factor c-Fos coordinates with histone lysine-specific demethylase 2A to activate the expression of cyclooxygenase-2

Shaoli Lu _, Yang Yang, Yipeng Du, Lin-lin Cao, Meiting Li, Changchun Shen, Tianyun Hou, Ying Zhao, Haiying Wang, Dajun Deng, Lina Wang, Qihua He and Wei-Guo Zhu

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Oncotarget. 2015; 6:34704-34717. https://doi.org/10.18632/oncotarget.5474

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Shaoli Lu1,*, Yang Yang1,*, Yipeng Du1, Lin-lin Cao1, Meiting Li1, Changchun Shen1, Tianyun Hou1, Ying Zhao1, Haiying Wang1, Dajun Deng2, Lina Wang1, Qihua He3, Wei-Guo Zhu1,4

1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China

2Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Beijing 100142, China

3Center of Medical and Health Analysis, Peking University Health Science Center, Beijing 100871, China

4Peking University-Tsinghua University Joint Center for Life Sciences, Beijing 100751, China

*These authors contributed equally to this work

Correspondence to:

Wei-Guo Zhu, e-mail: [email protected]

Yang Yang, e-mail: [email protected]

Keywords: COX-2, c-Fos, KDM2A, histone methylation

Received: April 28, 2015     Accepted: September 15, 2015     Published: September 25, 2015


Cyclooxygenase-2 (COX-2) is overexpressed in a variety of human epithelial cancers, including lung cancer, and is highly associated with a poor prognosis and a low survival rate. Understanding how COX-2 is regulated in response to carcinogens will offer insight into designing anti-cancer strategies and preventing cancer development. Here, we analyzed COX-2 expression in several human lung cancer cell lines and found that COX-2 expression was absent in the H719 and H460 cell lines by a DNA methylation-independent mechanism. The re-expression of COX-2 was observed after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment in both cell lines. Further investigation found that H3K36 dimethylation was significantly reduced near the COX-2 promoter because histone demethylase 2A (KDM2A) was recruited to the COX-2 promoter after TPA treatment. In addition, the transcription factor c-Fos was found to be required to recruit KDM2A to the COX-2 promoter for reactivation of COX-2 in response to TPA treatment in both the H719 and H460 cell lines. Together, our data reveal a novel mechanism by which the carcinogen TPA activates COX-2 expression by regulating H3K36 dimethylation near the COX-2 promoter.

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