title: Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis.
abstract: 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.
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.|Molecular Imaging Center, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.|Molecular Imaging Center, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Xia
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Juanfang
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Namei
authors.initials: N
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Hongde
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Xinfang
authors.initials: X
authors.lastname: Yu
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Hanyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Xinxian
authors.initials: X
authors.lastname: Weng
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, PR China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Key laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China.|Molecular Imaging Center, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D008517:Phytotherapy / Q000379:methods*; D060888:Real-Time Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013729:Terpenes; C058858:grifolin
keywords: DNMT1; ERK1/2; grifolin; metastasis