Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis.
The oncoprotein EZH2, as a histone H3K27 methyltransferase, is frequently overexpressed in various cancer types. However, the mechanisms underlying its role in urinary bladder cancer (UBC) cells have not yet fully understood. Herein, we reported that honokiol, a biologically active biphenolic compound isolated from the Magnolia officinalis inhibited human UBC cell proliferation, survival, cancer stemness, migration, and invasion, through downregulation of EZH2 expression level, along with the reductions of MMP9, CD44, Sox2 and the induction of tumor suppressor miR-143. Either EZH2 overexpression or miR-143 inhibition could partially reverse honokiol-induced cell growth arrest and impaired clonogenicity. Importantly, it was first revealed that EZH2 could directly bind to the transcriptional regulatory region of miR-143 and repress its expression. Furthermore, honokiol treatment on T24 tumor xenografts confirmed its anticancer effects in vivo, including suppression tumor growth and tumor stemness, accompanied by the dysregulation of EZH2 and miR-143 expressions. Our data suggest a promising therapeutic option to develop drugs targeting EZH2/miR-143 axis, such as honokiol, for bladder cancer treatment.
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
Qing
Q
Zhang
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Wei
W
Zhao
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
Changxiao
C
Ye
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
Junlong
J
Zhuang
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Cunjie
C
Chang
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Yuying
Y
Li
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Xiaojing
X
Huang
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Lan
L
Shen
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Yan
Y
Li
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Yangyan
Y
Cui
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
Jiannan
J
Song
Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China.
Bing
B
Shen
Amitabha Medical Clinic and Healing Center, Santa Rosa, CA, USA.
Isaac
I
Eliaz
SIBS (Institute of Health Sciences)-Changhai Hospital Joint Center for Translational Research, Institutes for Translational Research (CAS-SMMU), Shanghai, China.
Ruimin
R
Huang
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Hao
H
Ying
Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
Hongqian
H
Guo
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China.
Jun
J
Yan
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D000071221:Enhancer of Zeste Homolog 2 Protein; D018960:Hyaluronan Receptors; D017705:Lignans; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; D055748:SOXB1 Transcription Factors; C497483:CD44 protein, human; C542359:MIRN143 microRNA, human; C527782:SOX2 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C498409:EZH2 protein, human; C579270:MMP9 protein, human
EZH2; bladder cancer; honokiol; microRNA