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CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status

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Abstract

We previously reported that CG0006, a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI), suppresses the growth of human cancer cells. Here, we tested the ability of CG0006 to inhibit breast cancer cell proliferation in relation to estrogen receptor (ER) status, and examined changes in the expression of cell-cycle regulatory proteins. CG0006 effects on the proliferation of multiple human cancer cell lines were tested using MTT and MTS assays. Changes in estrogen-signaling proteins and cell-cycle regulatory proteins were examined by western blotting and quantitative RT-PCR, and cell-cycle effects were tested using flow cytometry. CG0006 increased histone H3 and H4 acetylation, up-regulated p21 protein, and promoted cell-cycle arrest, inducing G2/M-phase accumulation in ER-positive MCF7 cells, and G1- and G2/M-phase accumulation in ER-negative MDA-MB-231 cells. In both cell types, CG0006 treatment (1 μM) reduced the levels of the estrogen-signaling proteins ERα and cyclin D1, and promoted massive degradation of cell-cycle regulatory proteins. CG0006 down-regulated the histone deacetylase HDAC6 at the protein level in association with a subsequent increase in Hsp90 and α-tubulin acetylation. HDAC6 depletion using small interfering RNA produced a protein-degradation phenotype similar to that of CG0006 treatment. These findings suggest that CG0006 inhibits breast cancer cell growth by two different pathways: a histone acetylation-dependent pathway, and a non-epigenetic pathway that disrupts chaperone function.

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Acknowledgments

This work was supported by a grant (A062254) from the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea. This research was also supported by the Mid-career Researcher Program through an NRF grant funded by the MEST (No. 2009-0081016), and a grant from the Asan Institute for Life Science (2006-309).

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Authors and Affiliations

  1. Department of Pathology, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Hyun Mi Kim, Se Jin Jang & Jene Choi

  2. Department of Urology, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Choung-Soo Kim

  3. Department of Hematology, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Je-Hwan Lee

  4. Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Jung Jin Hwang

  5. Institute for Innovative Cancer Research, Asan Medical Center, 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Hyun Mi Kim, Choung-Soo Kim, Je-Hwan Lee, Se Jin Jang, Jung Jin Hwang & Jene Choi

  6. Crystal Genomics Inc., 388-1 Pungnap-2 dong, Songpa-gu, Seoul, 138-736, Korea

    Seonggu Ro & Young-Lan Hyun

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  1. Hyun Mi Kim
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Correspondence to Jene Choi.

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Kim, H.M., Kim, CS., Lee, JH. et al. CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status. Breast Cancer Res Treat 130, 365–375 (2011). https://doi.org/10.1007/s10549-010-1310-4

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