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Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors

Oncogene volume 35, pages 5515–5526 (2016)Cite this article

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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.

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Acknowledgements

We thank Dr Tomas Ekström (Karolinska Hospital, Sweden) to kindly provide the information on the structure and sequence of IGF2 promoters. This work was supported by grants from the National Research Foundation of Korea (NRF), the Ministry of Science, ICT and Future Planning (MSIP), Republic of Korea ((Nos. NRF-2011-0017639 and NRF-2011-0030001), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1520250)) and the National Institutes of Health (R01 CA100816).

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  1. S-C Lee and H-Y Min: These two authors contributed equally to this work and should be considered as first authors.

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    S-C Lee, H-Y Min, K H Park, S Y Hyun, J Cho, J K Woo & H-Y Lee

  2. Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea

    H J Jung & H-Y Lee

  3. College of Pharmacy, Inje University, Gimhae, Republic of Korea

    S J Kwon & H-J Lee

  4. Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    F M Johnson

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Lee, SC., Min, HY., Jung, H. et al. Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors. Oncogene 35, 5515–5526 (2016). https://doi.org/10.1038/onc.2016.92

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