title: Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors.
abstract: Histone deacetylase (HDAC) inhibitors (HDIs) are promising anticancer therapies and have been clinically used for the treatment of hematological malignancy. However, their efficacy in solid tumors is marginal and drug resistance hampers their further clinical utility. To develop novel strategies for the HDI-based anticancer therapeutics in non-small cell lung cancer (NSCLC), in the present study, we investigated the mechanisms underlying resistance to HDI treatment in NSCLC cells. We show the STAT3-mediated IGF2/IGF-1R signaling cascade as a key modulator for both acquired and primary HDI resistance. The treatment with HDI upregulated IGF2 transcription in NSCLC cells carrying intrinsic or acquired drug resistance via direct binding of STAT3 in IGF2 P3 and P4 promoters. Acetylated STAT3 emerged upon HDAC inhibition was protected from the proteasome-mediated degradation of STAT3 and functioned as a direct transcription factor for IGF2 expression. Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models. These findings provide new insights into the role of acetylated STAT3-mediated activation of IGF2 transcription in HDI resistance, suggesting IGF2 or STAT3 as novel targets to overcome HDI resistance in NSCLC.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Min
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Hyun
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: J K
authors.initials: JK
authors.lastname: Woo
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: F M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.|Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050796:STAT3 Transcription Factor; D000077337:Vorinostat; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1