TY - JOUR
T1 - Licochalcone A is a natural selective inhibitor of arginine methyltransferase 6
AU - Gong, Shuai
AU - Maegawa, Shinji
AU - Yang, Yanwen
AU - Gopalakrishnan, Vidya
AU - Zheng, Guangrong
AU - Cheng, Donghang
N1 - Funding Information:
This work was supported by the Addis Faith Foundation (V.G.) and NIH P20GM109005 (G.Z.).
Publisher Copyright:
© 2021 The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - Arginine methylation is a post-translational modification that is implicated in multiple biological functions including transcriptional regulation. The expression of protein arginine methyltransferases (PRMT) has been shown to be up-regulated in various cancers. PRMTs have emerged as attractive targets for the development of new cancer therapies. Here, we describe the identification of a natural compound, licochalcone A, as a novel, reversible and selective inhibitor of PRMT6. Since expression of PRMT6 is up-regulated in human breast cancers and is associated with oncogenesis, we used the human breast cancer cell line system to study the effect of licochalcone A treatment on PRMT6 activity, cell viability, cell cycle, and apoptosis. We demonstrated that licochalcone A is a non-Sadenosyl L-methionine (SAM) binding site competitive inhibitor of PRMT6. In MCF-7 cells, it inhibited PRMT6-dependent methylation of histone H3 at arginine 2 (H3R2), which resulted in a significant repression of estrogen receptor activity. Licochalcone A exhibited cytotoxicity towards human MCF-7 breast cancer cells, but not MCF-10A human breast epithelial cells, by up-regulating p53 expression and blocking cell cycle progression at G2/M, followed by apoptosis. Thus, licochalcone A has potential for further development as a therapeutic agent against breast cancer.
AB - Arginine methylation is a post-translational modification that is implicated in multiple biological functions including transcriptional regulation. The expression of protein arginine methyltransferases (PRMT) has been shown to be up-regulated in various cancers. PRMTs have emerged as attractive targets for the development of new cancer therapies. Here, we describe the identification of a natural compound, licochalcone A, as a novel, reversible and selective inhibitor of PRMT6. Since expression of PRMT6 is up-regulated in human breast cancers and is associated with oncogenesis, we used the human breast cancer cell line system to study the effect of licochalcone A treatment on PRMT6 activity, cell viability, cell cycle, and apoptosis. We demonstrated that licochalcone A is a non-Sadenosyl L-methionine (SAM) binding site competitive inhibitor of PRMT6. In MCF-7 cells, it inhibited PRMT6-dependent methylation of histone H3 at arginine 2 (H3R2), which resulted in a significant repression of estrogen receptor activity. Licochalcone A exhibited cytotoxicity towards human MCF-7 breast cancer cells, but not MCF-10A human breast epithelial cells, by up-regulating p53 expression and blocking cell cycle progression at G2/M, followed by apoptosis. Thus, licochalcone A has potential for further development as a therapeutic agent against breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=85099968744&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099968744&partnerID=8YFLogxK
U2 - 10.1042/BCJ20200411
DO - 10.1042/BCJ20200411
M3 - Article
C2 - 33245113
AN - SCOPUS:85099968744
SN - 0264-6021
VL - 478
SP - 389
EP - 406
JO - Biochemical Journal
JF - Biochemical Journal
IS - 2
ER -