Program Official

Principal Investigator

Ah-Ng Tony
Awardee Organization

Rutgers, The State Univ Of N.J.
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Prevention of skin cancer by phytochemicals via Nrf2 and epigenetics

Non-melanoma skin cancers are the most common types of cancers in the United States, with over 1 million new cases per year, while increasing exposure to sunlight (UV) and environmental carcinogens appear to be the major causative factors. The long term goal of this application is to develop a safe and effective strategy using relatively non-toxic dietary cancer chemopreventive compounds to prevent skin cancer. The rationale for these studies is based on investigation from our laboratory and others, showing that: (1) Sulforaphane (SFN) presents abundantly in these berries and crucifers, respectively, strongly inhibits skin carcinogenesis in various mouse models in vivo; (2) Skin carcinogenesis is greatly enhanced in knockouts of Nrf2, a transcription factor critical in mediating anti-oxidative stress/inflammatory responses, and, importantly, SFN has no cancer protective effect in these Nrf2(-/-) mice; (3) Nrf2 and Nrf2-targeted HO-1 expression is decreased in skin tumors in Nrf2(+/+) mice; (4) Enhanced expression of c-Myc, Bcl-2, cyclin D1, beta-catenin, VEGF, Cox-2, and Bax is seen in all skin tumors; (5) UVB enhanced expression of inflammatory biomarkers in the skin of Nrf2(-/-) mice is substantially decreased compared with Nrf2(+/+) mice; (6) SFN induces cellular antioxidant proteins in MEFs (mouse embryonic fibroblast) and MEKs (mouse epidermal keratinocytes) of Nrf2 (+/+) but not of Nrf2 (- /-); (7) SFN blocks TPA-induced ear inflammation in C57BL/6J mice and not in Nrf2(-/-) mice; (8) Ursolic acid (UA), a natural triterpenoid with potent anti-inflammatory and cancer preventive activities inhibits TPA-induced ear edema and tumor promotion; (9) Increasing evidence suggests that epigenetics plays an important role in cancer development and progression including non-melanoma skin cancer; both UA and SFN modify CpG methylation of Nrf2 in JB6 mouse epidermal cell line; (10) Significant difference are observed in global DNA methylation profiles between DMBA/TPA papilloma vs normal skin and UVB-induced skin tumor vs non- irradiated skin analyzed by MeDIP-Seq analysis; and (11) UA and SFN inhibit TPA-induced JB6 transformation in soft agar. Based on the results summarized above we hypothesize that UA and SFN prevent skin carcinogenesis by altering epigenetic modifications with 3 specific aims: (1) To investigate the epigenetic events during in vivo skin cancer development and progression in B[a]P/TPA-induced skin carcinogenesis in Nrf2(+/+) vs Nrf2(-/-) C57BL6 mice, UVB-induced skin tumorigenesis in SKH-1 mice, and the cancer preventive efficacy coupled with epigenetic changes of UA and SFN; (2) To examine the epigenetic changes during transformation in vitro of mouse epidermal JB6 and human keratinocyte HaCaT cells and the effect of UA and SFN on these epigenetic changes; (3) To elucidate the molecular mechanisms involved in the epigenetic regulation of inflammatory/oxidative stress genes identified in Aims 1 and 2 by UA and SFN in mouse epidermal JB6 and human keratinocyte HaCaT cells. This study will advance our knowledge in developing better chemopreventive compounds for cancer chemoprevention clinical trials in skin cancer.


  • Li S, Li W, Wang C, Wu R, Yin R, Kuo HC, Wang L, Kong AN. Pelargonidin reduces the TPA induced transformation of mouse epidermal cells -potential involvement of Nrf2 promoter demethylation. Chemico-biological interactions. 2019 Aug 25;309:108701. Epub 2019 Jun 7. PMID: 31181187
  • Nair S, Kong AT. Emerging roles for clinical pharmacometrics in cancer precision medicine. Current pharmacology reports. 2018 Jun;4(3):276-283. Epub 2018 Apr 20. PMID: 30345221
  • Yang Y, Yin R, Wu R, Ramirez CN, Sargsyan D, Li S, Wang L, Cheng D, Wang C, Hudlikar R, Kuo HC, Lu Y, Kong AN. DNA methylome and transcriptome alterations and cancer prevention by triterpenoid ursolic acid in UVB-induced skin tumor in mice. Molecular carcinogenesis. 2019 Oct;58(10):1738-1753. Epub 2019 Jun 25. PMID: 31237383
  • Chou PJ, Sarwar MS, Wang L, Wu R, Li S, Hudlikar RR, Wang Y, Su X, Kong AN. Metabolomic, DNA Methylomic, and Transcriptomic Profiling of Suberoylanilide Hydroxamic Acid Effects on LPS-Exposed Lung Epithelial Cells. Cancer prevention research (Philadelphia, Pa.). 2023 Jun 1;16(6):321-332. PMID: 36867722
  • Li W, Guo Y, Zhang C, Wu R, Yang AY, Gaspar J, Kong AN. Dietary Phytochemicals and Cancer Chemoprevention: A Perspective on Oxidative Stress, Inflammation, and Epigenetics. Chemical research in toxicology. 2016 Dec 19;29(12):2071-2095. Epub 2016 Dec 5. PMID: 27989132
  • Yin R, Kuo HC, Hudlikar R, Sargsyan D, Li S, Wang L, Wu R, Kong AN. Gut microbiota, dietary phytochemicals and benefits to human health. Current pharmacology reports. 2019;5:332-344. Epub 2019 Aug 19. PMID: 33224717
  • Wang C, Wu R, Sargsyan D, Zheng M, Li S, Yin R, Su S, Raskin I, Kong AN. CpG methyl-seq and RNA-seq epigenomic and transcriptomic studies on the preventive effects of Moringa isothiocyanate in mouse epidermal JB6 cells induced by the tumor promoter TPA. The Journal of nutritional biochemistry. 2019 Jun;68:69-78. Epub 2019 Mar 28. PMID: 31030169
  • Wu R, Wang L, Kuo HD, Shannar A, Peter R, Chou PJ, Li S, Hudlikar R, Liu X, Liu Z, Poiani GJ, Amorosa L, Brunetti L, Kong AN. An Update on Current Therapeutic Drugs Treating COVID-19. Current pharmacology reports. 2020;6(3):56-70. Epub 2020 May 11. PMID: 32395418
  • Zhang C, Wang C, Li W, Wu R, Guo Y, Cheng D, Yang Y, Androulakis IP, Kong AN. Pharmacokinetics and Pharmacodynamics of the Triterpenoid Ursolic Acid in Regulating the Antioxidant, Anti-inflammatory, and Epigenetic Gene Responses in Rat Leukocytes. Molecular pharmaceutics. 2017 Nov 6;14(11):3709-3717. Epub 2017 Oct 25. PMID: 29035547
  • Kong AN, Lau ATY, Brunetti L. Hot Topic Commentary on COVID-19. Current pharmacology reports. 2020;6(3):53-55. Epub 2020 May 11. PMID: 32395419
  • Li S, Kuo HD, Yin R, Wu R, Liu X, Wang L, Hudlikar R, Peter RM, Kong AN. Epigenetics/epigenomics of triterpenoids in cancer prevention and in health. Biochemical pharmacology. 2020 May;175:113890. Epub 2020 Feb 29. PMID: 32119837
  • Hudlikar R, Wang L, Wu R, Li S, Peter R, Shannar A, Chou PJ, Liu X, Liu Z, Kuo HD, Kong AN. Epigenetics/Epigenomics and Prevention of Early Stages of Cancer by Isothiocyanates. Cancer prevention research (Philadelphia, Pa.). 2021 Feb;14(2):151-164. Epub 2020 Oct 14. PMID: 33055265
  • Li S, Li W, Wu R, Yin R, Sargsyan D, Raskin I, Kong AN. Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy. The AAPS journal. 2019 Dec 5;22(1):8. PMID: 31807911
  • Yang Y, Yang I, Cao M, Su ZY, Wu R, Guo Y, Fang M, Kong AN. Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells. The AAPS journal. 2018 Feb 20;20(2):32. PMID: 29603113
  • Kim H, Ramirez CN, Su ZY, Kong AN. Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells. The Journal of nutritional biochemistry. 2016 Jul;33:54-62. Epub 2015 Sep 28. PMID: 27260468
  • Ramirez CN, Li W, Zhang C, Wu R, Su S, Wang C, Gao L, Yin R, Kong AN. In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention. The AAPS journal. 2017 Dec 20;20(1):19. PMID: 29264822
  • Wu R, Li S, Sargsyan D, Yin R, Kuo HC, Peter R, Wang L, Hudlikar R, Liu X, Kong AN. DNA methylome, transcriptome, and prostate cancer prevention by phenethyl isothiocyanate in TRAMP mice. Molecular carcinogenesis. 2021 Jun;60(6):391-402. Epub 2021 Apr 13. PMID: 33848375
  • Wang C, Feng Y, Zhang C, Cheng D, Wu R, Yang Y, Sargsyan D, Kumar D, Kong AN. PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Jan;34(1):1304-1318. Epub 2019 Nov 29. PMID: 31914691
  • Wang C, Shu L, Zhang C, Li W, Wu R, Guo Y, Yang Y, Kong AN. Histone Methyltransferase Setd7 Regulates Nrf2 Signaling Pathway by Phenethyl Isothiocyanate and Ursolic Acid in Human Prostate Cancer Cells. Molecular nutrition & food research. 2018 Sep;62(18):e1700840. Epub 2018 Mar 6. PMID: 29383876
  • Kuo HD, Wu R, Li S, Yang AY, Kong AN. Anthocyanin Delphinidin Prevents Neoplastic Transformation of Mouse Skin JB6 P+ Cells: Epigenetic Re-activation of Nrf2-ARE Pathway. The AAPS journal. 2019 Jun 28;21(5):83. PMID: 31254216
  • Wu R, Wang L, Yin R, Hudlikar R, Li S, Kuo HD, Peter R, Sargsyan D, Guo Y, Liu X, Kong AN. Epigenetics/epigenomics and prevention by curcumin of early stages of inflammatory-driven colon cancer. Molecular carcinogenesis. 2020 Feb;59(2):227-236. Epub 2019 Dec 9. PMID: 31820492
  • Wang L, Wu R, Sargsyan D, Su S, Kuo HC, Li S, Chou P, Sarwar MS, Phadnis A, Wang Y, Su X, Kong AN. Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin. The AAPS journal. 2022 Jan 18;24(1):30. PMID: 35043283
  • Ramirez CN, Li W, Zhang C, Wu R, Su S, Wang C, Gao L, Yin R, Kong AT. Correction to: In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention. The AAPS journal. 2018 Feb 6;20(2):27. PMID: 29411155
  • Sarwar MS, Ramirez CN, Dina Kuo HC, Chou P, Wu R, Sargsyan D, Yang Y, Shannar A, Mary Peter R, Yin R, Wang Y, Su X, Kong AN. The environmental carcinogen benzo[a]pyrene regulates epigenetic reprogramming and metabolic rewiring in a two-stage mouse skin carcinogenesis model. Carcinogenesis. 2023 Aug 10;44(5):436-449. PMID: 37100755
  • Li W, Su ZY, Guo Y, Zhang C, Wu R, Gao L, Zheng X, Du ZY, Zhang K, Kong AN. Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells. Chemical research in toxicology. 2018 Feb 19;31(2):88-96. Epub 2018 Jan 8. PMID: 29228771
  • Zhang C, Su ZY, Wang L, Shu L, Yang Y, Guo Y, Pung D, Bountra C, Kong AN. Epigenetic blockade of neoplastic transformation by bromodomain and extra-terminal (BET) domain protein inhibitor JQ-1. Biochemical pharmacology. 2016 Oct 1;117:35-45. Epub 2016 Aug 9. PMID: 27520485
  • Li S, Dina Kuo HC, Wang L, Wu R, Sargsyan D, Kong AN. UVB Drives Metabolic Rewiring and Epigenetic Reprograming and Protection by Sulforaphane in Human Skin Keratinocytes. Chemical research in toxicology. 2022 Jul 18;35(7):1220-1233. Epub 2022 Jun 14. PMID: 35700067
  • Huang Y, Li W, Su ZY, Kong AN. The complexity of the Nrf2 pathway: beyond the antioxidant response. The Journal of nutritional biochemistry. 2015 Dec;26(12):1401-13. Epub 2015 Aug 8. PMID: 26419687
  • Cheng D, Wu R, Guo Y, Kong AN. Regulation of Keap1-Nrf2 signaling: The role of epigenetics. Current opinion in toxicology. 2016 Dec;1:134-138. Epub 2016 Nov 5. PMID: 29057383
  • Yang Y, Wu R, Sargsyan D, Yin R, Kuo HC, Yang I, Wang L, Cheng D, Wang C, Li S, Hudlikar R, Lu Y, Kong AN. UVB drives different stages of epigenome alterations during progression of skin cancer. Cancer letters. 2019 May 1;449:20-30. Epub 2019 Feb 13. PMID: 30771437
  • Li S, Wu R, Wang L, Dina Kuo HC, Sargsyan D, Zheng X, Wang Y, Su X, Kong AN. Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer. Molecular carcinogenesis. 2022 Jan;61(1):111-121. Epub 2021 Nov 2. PMID: 34727410
  • Boyanapalli SS, Li W, Fuentes F, Guo Y, Ramirez CN, Gonzalez XP, Pung D, Kong AN. Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells. Pharmacological research. 2016 Dec;114:175-184. Epub 2016 Nov 3. PMID: 27818231
  • Kuo HD, Wu R, Sarwar MS, Zheng M, Wang C, Sargsyan D, Suh N, Kong AT. DNA Methylome and Transcriptome Study of Triterpenoid CDDO in TPA-Mediated Skin Carcinogenesis Model. The AAPS journal. 2022 Nov 2;24(6):115. PMID: 36324037
  • Li S, Yang Y, Sargsyan D, Wu R, Yin R, Kuo HD, Yang I, Wang L, Cheng D, Ramirez CN, Hudlikar R, Lu Y, Kong AN. Epigenome, Transcriptome, and Protection by Sulforaphane at Different Stages of UVB-Induced Skin Carcinogenesis. Cancer prevention research (Philadelphia, Pa.). 2020 Jun;13(6):551-562. Epub 2020 Mar 11. PMID: 32161072
  • Hudlikar RR, Sargsyan D, Wu R, Su S, Zheng M, Kong AN. Triterpenoid corosolic acid modulates global CpG methylation and transcriptome of tumor promotor TPA induced mouse epidermal JB6 P+ cells. Chemico-biological interactions. 2020 Apr 25;321:109025. Epub 2020 Mar 3. PMID: 32135139
  • Wu R, Li S, Hudlikar R, Wang L, Shannar A, Peter R, Chou PJ, Kuo HD, Liu Z, Kong AN. Redox signaling, mitochondrial metabolism, epigenetics and redox active phytochemicals. Free radical biology & medicine. 2022 Feb 1;179:328-336. Epub 2020 Dec 24. PMID: 33359432