Epidermal squamous cell carcinoma is one of the most common forms of human cancer and the incidence is increasing. Thus, skin cancer is an important health concern and advanced disease recurs and is life- threatening and disfiguring. Because skin cancer development involves multiple events over a long period of time, prevention is an important and preferred option. For this reason there is a major ongoing effort to identify preventive agents that can be taken orally or applied on the skin surface. In particula, we have focused on the impact of sulforaphane (SFN), derived from broccoli, on function of the Ezh2 Polycomb Group (PcG) protein. PcG proteins are important epigenetic regulators that methylate and ubiquitinate specific histones to produce closed chromatin and silence tumor suppressor gene expression. Key polycomb group proteins, including Ezh2, are overexpressed in skin cancer and this drives silencing of p21Cip1 and other tumor suppressors leading to enhanced tumor cell survival. We have shown that SFN suppresses Ezh2 which leads to increased p21Cip1 expression. These changes ultimately lead to cessation of skin cancer cell proliferation and increased cancer cell death. Our exciting unpublished preliminary studies suggest that a pathway that includes two master regulators of keratinocyte survival and stem cell fate, DNp63a and KLF4, regulates Ezh2 level. These proteins have not been previously considered as important prevention targets. We hypothesize that in cancer cells a DNp63a, KLF4 pathway stimulates Ezh2 gene expression which, in turn, acts to reduce p21Cip1 expression leading to increased cancer cell survival. We further propose that SFN inhibits events in this pathway to reduce Ezh2 expression and increase tumor suppressor expression. Experiments in this proposal revolve around well-defined translation-relevant goals.
Specific Aim 1 studies how DNp63a and KLF4 regulate Ezh2 level.
Specific Aims 2 examines SFN regulation of this pathway.
Specific Aim 3 examines Ezh2 regulation of p21Cip1 expression, and Specific Aim 4 address the impact of Ezh2 and SFN treatment on tumor formation in vivo. These studies are highly relevant to understanding the biological role of SFN in preventing skin cancer formation.

Public Health Relevance

Epidermal squamous cell carcinoma ranks among the most common forms of human cancer and is an important health concern. Because skin cancer develops over a long period of time, prevention is an important and preferred option to reduce skin cancer rate. Polycomb proteins are important epigenetic regulators of gene expression that are highly overexpressed in skin cancer and act to enhance skin cancer cell survival. In the present study we examine the mechanism whereby sulforaphane, a dietary agent derived from broccoli, reduces expression of polycomb group proteins leading to enhanced cancer cell death.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131074-07
Application #
8689969
Study Section
Special Emphasis Panel (ZRG1-OTC-K (03))
Program Officer
Ross, Sharon A
Project Start
2007-12-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
$413,155
Indirect Cost
$143,998
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
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
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
Fisher, Matthew L; Kerr, Candace; Adhikary, Gautam et al. (2016) Transglutaminase Interaction with ?6/?4-Integrin Stimulates YAP1-Dependent ?Np63? Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation. Cancer Res 76:7265-7276
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

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