Histone modification by Polycomb Group (PcG) proteins is an epigenetic mechanism of paramount importance that controls gene expression by modifying chromatin structure to open or close (silence) genes. This system includes two regulatory complexes, PRC2 and PRC1. PRC2 binds to chromatin and deacetylates and then methylates histone H3 at lysine 27. These events are catalyzed by the PRC2 protein Ezh2, a histone methyltransferase. The trimethylated lysine (H3 K27-3M) then serves as a binding site for the Bmi-1 protein of the PRC1 complex which binds to alter chromatin structure and gene expression. Our ongoing studies in cultured human skin cancer cells demonstrate that treatment with the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), reduces expression of the Bmi-1 and Ezh2 PcG proteins. We propose that chemopreventive agents reduce PcG protein level and activity leading to reduced cell survival. The parent grant focuses on human skin cancer cell lines and a murine skin carcinogenesis models. However, the primary target of carcinogen and chemopreventive agent action is normal human epidermis. Thus, this competitive revision proposal adds a physiological model of human epidermis to our experiments. This new direction will greatly facilitate study of the interplay between EGCG, PcG protein function and response to UVB challenge. The goal of this Competitive Supplement is to examine whether EGCG modulates PcG protein function to attenuate the impact of UVB irradiation using an """"""""epidermal raft culture"""""""" system that mimics in vivo skin cell differentiation, and can be engrafted onto mouse dermis as a model to study in vivo behavior of human skin. These models mimic normal human skin biology. These studies significantly extend and expand the power and scope of our study. We argue that these studies are appropriate based on our progress on the parent grant. We hypothesize that Bmi-1 and Ezh2 PcG proteins enhance keratinocyte survival and protect against challenge with UVB or chemopreventive agent and that down-regulation of these proteins by EGCG protects against UVB-dependent cancer. These studies will provide important insights regarding the role of EGCG in cancer prevention using preclinical in vivo models of human epidermal differentiation.

Public Health Relevance

Skin cancer is an important health problem and is a major cause of cancer worldwide. Skin cancer chemoprevention by diet-derived agents is an important area of study. In the present proposal we study the ability of green tea polyphenols to regulate epigenetic events to improve the outcome in ultraviolet-light induced skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA131074-02S1
Application #
7812316
Study Section
Special Emphasis Panel (ZRG1-OTC-N (95))
Program Officer
Milner, John A
Project Start
2007-12-01
Project End
2011-09-29
Budget Start
2009-09-30
Budget End
2011-09-29
Support Year
2
Fiscal Year
2009
Total Cost
$349,914
Indirect Cost
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kerr, Candace; Adhikary, Gautam; Grun, Daniel et al. (2018) Combination cisplatin and sulforaphane treatment reduces proliferation, invasion, and tumor formation in epidermal squamous cell carcinoma. Mol Carcinog 57:3-11
Young, Christina A; Eckert, Richard L; Adhikary, Gautam et al. (2017) Embryonic AP1 Transcription Factor Deficiency Causes a Collodion Baby-Like Phenotype. J Invest Dermatol 137:1868-1877
Kerr, C; Szmacinski, H; Fisher, M L et al. (2017) Transamidase site-targeted agents alter the conformation of the transglutaminase cancer stem cell survival protein to reduce GTP binding activity and cancer stem cell survival. Oncogene 36:2981-2990
Young, Christina A; Rorke, Ellen A; Adhikary, Gautam et al. (2017) Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype. Cell Death Dis 8:e2840
Saha, Kamalika; Fisher, Matthew L; Adhikary, Gautam et al. (2017) Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation. Carcinogenesis 38:827-836
Fisher, Matthew L; Adhikary, Gautam; Kerr, Candace et al. (2017) Transglutaminase 2 Is a Direct Target Gene of YAP-TAZ-Response. Cancer Res 77:4736
Fisher, Matthew L; Ciavattone, Nicholas; Grun, Daniel et al. (2017) Sulforaphane reduces YAP/?Np63? signaling to reduce cancer stem cell survival and tumor formation. Oncotarget 8:73407-73418
Saha, Kamalika; Adhikary, Gautam; Eckert, Richard L (2016) MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKC?/p38? Signaling. J Invest Dermatol 136:214-224
Grun, D; Adhikary, G; Eckert, R L (2016) VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors. Oncogene 35:4379-87
Fisher, Matthew L; Adhikary, Gautam; Grun, Dan et al. (2016) The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane. Mol Carcinog 55:2024-2036

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