Epidermal cancer stem (ECS) cells are important potential targets of dietary cancer prevention agents. We have developed in vitro and in vivo cultivation systems that allow propagation of human ECS cells from squamous cell carcinoma. Using this system, we show that ECS cells display markedly enhanced sensitivity to treatment with dietary cancer prevention agent, sulforaphane (SFN), as compared to non-stem cancer cells. We propose that ECS cell subpopulation of tumor cells is selectively targeted by sulforaphane. We further show that expression of the polycomb group (PcG) stem cell maintenance protein, Ezh2, is markedly elevated in the ECS cell population and that SFN treatment suppresses the level of this regulator. We hypothesize that ECS cells are ultra-sensitive to SFN, compared to non-stem cancer cells, and that SFN reduces Ezh2 protein level and function thereby altering downstream target gene expression to reduce ECS cell survival. We further hypothesize that Ezh2 controls tumor cell production of angiogenic factors that drive tumor vascularization to permit rapid tumor expansion, and that SFN inhibits this. However, we do not have a good understanding of this regulation. First, what is the role of Ezh2 as a mediator of enhanced stem cell sensitivity to SFN and is suppression of Ezh2 protein function required for SFN-dependent suppression of cancer stem cell survival? Second, we do not know if ECS cells will display a similar enhanced SFN sensitivity in vivo and so it will be important to test. Third, we do not know the mechanism whereby Ezh2 and SFN influence tumor cell production of angiogenic agents to drive endothelial cell-dependent tumor vascularization. Our goal is to characterize the sulforaphane anti-stem cell mechanism of action with an ultimate goal of developing sulforaphane as an epidermal stem cell-directed cancer prevention agent.

Public Health Relevance

Epidermal cancer stem (ECS) cells are important potential targets of dietary cancer prevention agents. We have developed in vitro and in vivo cultivation systems that allow propagation of human squamous cell carcinoma stem cells. We show that these cells display markedly increased sensitivity to treatment with dietary cancer prevention agent, sulforaphane, as compared to non-stem cells. We propose that skin cancer stem cells are an important target of sulforaphane for prevention of epidermal cancer development. Our goal is to characterize the sulforaphane anti-stem cell mechanism of action with an ultimate goal of developing sulforaphane as an epidermal stem cell-directed epidermal cancer prevention agent.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184027-04
Application #
9458125
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kim, Young S
Project Start
2015-04-03
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
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
Hwang, Bor-Jang; Adhikary, Gautam; Eckert, Richard L et al. (2018) Chk1 inhibition as a novel therapeutic strategy in melanoma. Oncotarget 9:30450-30464
Adhikary, Gautam; Grun, Daniel; Alexander, H Richard et al. (2018) Transglutaminase is a mesothelioma cancer stem cell survival protein that is required for tumor formation. Oncotarget 9:34495-34505
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
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
Akbar, Abdullah; McNeil, Nicole M R; Albert, Marie R et al. (2017) Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase. J Med Chem 60:7910-7927
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; 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

Showing the most recent 10 out of 20 publications