Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis
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Xiangjian Luo1,2,*, Lifang Yang1,2,*, Lanbo Xiao1, Xiaofeng Xia3, Xin Dong1, Juanfang Zhong1, Ying Liu1, Namei Li1, Ling Chen1, Hongde Li1, Wei Li1, Wenbin Liu1, Xinfang Yu1, Hanyong Chen4, Min Tang1, Xinxian Weng1, Wei Yi1, Ann Bode4, Zigang Dong4, Jikai Liu5, Ya Cao1,2
1Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China
2Molecular Imaging Center, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China
3Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA
4The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
5State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, PR China
*These authors have contributed equally to this work
Xiangjian Luo, e-mail: [email protected]
Jikai Liu, e-mail: [email protected]
Ya Cao, e-mail: [email protected]
Keywords: grifolin, ERK1/2, DNMT1, metastasis
Received: May 16, 2015 Accepted: October 14, 2015 Published: October 26, 2015
Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been reported by us and others to display potent antitumor effects. However, the molecular target of grifolin has not been identified and the underlying mechanism of action is not fully understood. Here, we report that the ERK1/2 protein kinases are direct molecular targets of grifolin. Molecular modeling, affinity chromatography and fluorescence quenching analyses showed that grifolin directly binds to ERK1/2. And in vitro and ex vivo kinase assay data further demonstrated that grifolin inhibited the kinase activities of ERK1/2. We found that grifolin suppressed adhesion, migration and invasion of high-metastatic cancer cells. The inhibitory effect of grifolin against tumor metastasis was further confirmed in a metastatic mouse model. We found that grifolin decreased phosphorylation of Elk1 at Ser383, and the protein as well as the mRNA level of DNMT1 was also down-regulated. By luciferase reporter and ChIP assay analyses, we confirmed that grifolin inhibited the transcription activity of Elk1 as well as its binding to the dnmt1 promoter region. Moreover, we report that significant increases in the mRNA levels of Timp2 and pten were induced by grifolin. Thus, our data suggest that grifolin exerts its anti-tumor activity by epigenetic reactivation of metastasis inhibitory-related genes through ERK1/2-Elk1-DNMT1 signaling. Grifolin may represent a promising therapeutic lead compound for intervention of cancer metastasis, and it may also be useful as an ERK1/2 kinase inhibitor as well as an epigenetic agent to further our understanding of DNMT1 function.
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