title: Essential Role of DNA Methyltransferase 1-mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors.
abstract: Purpose:Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.Experimental Design:The methylation status of CCCTC-binding factor (CTCF)-binding sites in theIGF2/H19imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model.Results:HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation ofDNMT1DNMT1-mediated hypermethylation of CTCF-binding sites in theIGF2/H19ICR decreased CTCF insulator activity, leading to a transcriptional upregulation ofIGF2and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired orde novovorinostat resistance. Strategies targeting DNMT1 diminished theIGF2expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in theH19/IGF2ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies.Conclusions:DNMT1-mediated transcriptional upregulation ofIGF2is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of theH19/IGF2ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies.Clin Cancer Res; 23(5); 1299-311. ©2016 AACR.
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi 16229, Republic of Korea.
authors: Hye-Young
authors: HY
authors: Min
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Su-Chan
authors: SC
authors: Lee
authors: Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors: Jong Kyu
authors: JK
authors: Woo
authors: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
authors: Hyun Jin
authors: HJ
authors: Jung
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors: Kwan Hee
authors: KH
authors: Park
authors: College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Hae Min
authors: HM
authors: Jeong
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Seung Yeob
authors: SY
authors: Hyun
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Jaebeom
authors: J
authors: Cho
authors: College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Wooin
authors: W
authors: Lee
authors: College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Ji Eun
authors: JE
authors: Park
authors: College of Pharmacy, Inje University, Gimhae, Gyungnam 50834, Republic of Korea.
authors: So Jung
authors: SJ
authors: Kwon
authors: College of Pharmacy, Inje University, Gimhae, Gyungnam 50834, Republic of Korea.
authors: Hyo-Jong
authors: HJ
authors: Lee
authors: Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Xiao
authors: X
authors: Ni
authors: College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Young Kee
authors: YK
authors: Shin
authors: Department of Thoracic Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Faye M
authors: FM
authors: Johnson
authors: Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Madeleine
authors: M
authors: Duvic
authors: Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi 16229, Republic of Korea.|Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.|Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.|College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors: Ho-Young
authors: HY
authors: Lee
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C094335:H19 long non-coding RNA; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077337:Vorinostat; D007335:Insulin-Like Growth Factor II; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D006655:Histone Deacetylases