Abstract 5266: Metabolic rewiring and epigenetic reprogramming by the environmental carcinogen benzo[a]pyrene in a two-stage skin carcinogenesis mouse model and cancer interception by triterpenoid ursolic acid
Authors: Sarwar Md. Shahid , Ramirez Christina N. , Kuo Hsiao-Chen Dina , Chou Pochung , Wu Renyi , Sargsyan Davit , Shannar Ahmad , Peter Rebecca Mary , Yin Ran , Wang Yujue , Su Xiaoyang , Kong Ah-Ng 
Published: April 2023

Abstract
Nonmelanoma skin cancer (NMSC) is the most common skin cancer burden on the U.S. population. Environmental exposure to chemical carcinogens is one of the major causes of NMSC initiation, promotion, and progression. Ursolic acid (UA) is a naturally abundant pentacyclic triterpenoid showing anticancer potentials against diverse cancers. In the current study, we developed a two-stage skin carcinogenesis model in SKH1 hairless mice by administering cancer-initiating agent benzo[a]pyrene (B[a]P) and promoting agent 12-O-tetra-decanoylphorbol-13-acetate to study the epigenetic, transcriptomic, and metabolic changes at different stages (5, 20, and 26 weeks) during the development of NMSC, and investigated how UA regulates B[a]P-mediated alterations for NMSC interception. We found that UA protects against B[a]P-induced tumorigenesis at different phases of NMSC. Epigenetic CpG methyl-seq showed UA abrogated B[a]P-mediated alterations in differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq data exhibited UA reversed the differentially expressed genes (DEGs) of several inflammatory genes, such as chemokine ligand 8 (Ccl8) and interleukin 17F (Il17f), and epigenetic genes, such as DNA-methyltransferase 3-like (Dnmt3l) and protein-l-isoaspartate O-methyltransferase domain-containing protein 1 (Pcmtd1) during different stages of NMSC. Association study between DEGs and DMRs showed that B[a]P promoted transcription of kallikrein-related peptidase 13 (Klk13) by promoter demethylation, while UA suppressed Klk13 expression through hypermethylation in the promoter during the initiation stage, indicating the early intervention of UA. Ingenuity pathway analysis further showed significant upregulation of macrophage-stimulating protein-recepteur d'origine nantais (MSP-RON) signaling pathway by B[a]P during the initiation stage while suppressed by UA treatment. The metabolomic study revealed UA modulated cancer-associated changes in metabolisms, including the TCA cycle and pyruvate metabolism/metabolites during the promotion phase, indicating UA plays a critical role in regulating B[a]P-regulated metabolic changes and intercepting NMSC progression. In summary, UA protects against the environmental carcinogen B[a]P-driven epigenetic, transcriptomic, and metabolic changes during the initiation, promotion, and progression of NMSC, potentially contributing to the anticancer effects of UA. (Supported by NIH R01 CA200129 to A.N.K)
Citation Format: Md. Shahid Sarwar, Christina N. Ramirez, Hsiao-Chen Dina Kuo, Pochung Chou, Renyi Wu, Davit Sargsyan, Ahmad Shannar, Rebecca Mary Peter, Ran Yin, Yujue Wang, Xiaoyang Su, Ah-Ng Kong. Metabolic rewiring and epigenetic reprogramming by the environmental carcinogen benzo[a]pyrene in a two-stage skin carcinogenesis mouse model and cancer interception by triterpenoid ursolic acid. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5266.