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Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

Oncogene volume 22, pages 6023–6031 (2003)Cite this article

Abstract

We previously reported that the activation of p21WAF1/Cip1 transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKCɛ dominant-negative mutant, and antisense oligonucleotide to inhibit PKCɛ specifically, we found that among PKC isoforms, PKCɛ was required for the p21WAF1/Cip1 expression by apicidin. In addition to PKCɛ, PI 3-kinase appeared to participate in the activation of p21WAF1/Cip1 promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21WAF1/Cip1 promoter and p21WAF1/Cip1 protein expression by apicidin. Furthermore, membrane translocation of PKCɛ in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKCɛ in the p21WAF1/Cip1 promoter activation by apicidin. However, the p21WAF1/Cip1 expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21WAF1/Cip1 promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21WAF1/Cip1 by apicidin. Taken together, these results suggest that the PI 3-kinase–PKCɛ signaling pathway plays a pivotal role in the expression of the p21WAF1/Cip1 by apicidin.

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Abbreviations

HDAC:

histone deacetylase

PKC:

protein kinase C

Cdk:

cyclin-dependent kinase

TSA:

trichostatin A

NaB:

sodium butyrate

SAHA:

suberoylanilide hydroxamic acid

PDBu:

phorbol-dibutyrate

ERK:

extracellular-regulated protein kinase

PKA:

protein kinase A

MAPK:

mitogen-activated protein kinase

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Acknowledgements

This work was supported by Grant No. R01-2002-000-00213-0 from the Basic Research Program of the Korea Science and Engineering Foundation. We thank Dr Y Sowa (Kyoto Prefectural University of Medicine) for giving us the pWP101 reporter gene, Dr G Thiel (Medical Biochemistry and Molecular Biochemistry, University of the Saarland Medical Center) for delta-Sp1, Dr A Toker (Boston Biomedical Research Inst., Harvard Medical School) for PKCɛ-KW, and Dr M Wymann (Institute of Biochemistry, University of Fribourg, Switzerland) for PI3K-KR.

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  1. Yong Kee Kim and Jeung-Whan Han: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea

    Yong Kee Kim, Jeung-Whan Han, Yun Na Woo, Jae Kwang Chun, Ji Yeon Yoo, Eun-Jung Cho & Hyang-Woo Lee

  2. Department of Genetic Engineering, Sungkyunkwan University, Suwon, 440-746, Korea

    Sungyoul Hong

  3. Department of Pharmacology, College of Medicine, Konyang University, Nonsan, 320-711, Korea

    Hoi Young Lee

  4. School of Agricultural Biotechnology, Seoul National University, Suwon, 441-744, Korea

    Yin-Won Lee

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Kim, Y., Han, JW., Woo, Y. et al. Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway. Oncogene 22, 6023–6031 (2003). https://doi.org/10.1038/sj.onc.1206875

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