TY - JOUR
T1 - Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer
AU - Li, Shanyi
AU - Wu, Renyi
AU - Wang, Lujing
AU - Dina Kuo, Hsiao Chen
AU - Sargsyan, Davit
AU - Zheng, Xi
AU - Wang, Yujue
AU - Su, Xiaoyang
AU - Kong, Ah Ng
N1 - Funding Information:
This study was supported in part by R01AT009152 from the National Center for Complementary and Integrative Health (NCCIH) and R01CA200129 from the National Cancer Institute (NCI) (AK) and NIH grants P30CA072720‐5923 (XS). We thank all members of Dr. Ah‐Ng Kong's lab for helpful discussions and preparation of the manuscript.
Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2022/1
Y1 - 2022/1
N2 - Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography–mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.
AB - Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography–mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.
KW - cancer
KW - epigenome
KW - metabolome
KW - transcriptome
KW - ursolic acid
UR - http://www.scopus.com/inward/record.url?scp=85118350569&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118350569&partnerID=8YFLogxK
U2 - 10.1002/mc.23365
DO - 10.1002/mc.23365
M3 - Article
C2 - 34727410
AN - SCOPUS:85118350569
SN - 0899-1987
VL - 61
SP - 111
EP - 121
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 1
ER -