Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis.

Abstract

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.

• Authors: Qing Zhang, Wei Zhao, Changxiao Ye, Junlong Zhuang, Cunjie Chang, Yuying Li, Xiaojing Huang, Lan Shen, Yan Li, Yangyan Cui, Jiannan Song, Bing Shen, Isaac Eliaz, Ruimin Huang, Hao Ying, Hongqian Guo, Jun Yan
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37335-48 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26484567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Biphenyl Compounds
• CD44 protein, human
• Hyaluronan Receptors
• Lignans
• MIRN143 microRNA, human
• MicroRNAs
• SOX2 protein, human
• SOXB1 Transcription Factors
• honokiol
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Binding Sites
• Biphenyl Compounds (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation
• Enhancer of Zeste Homolog 2 Protein
• Gene Expression Regulation, Neoplastic
• Humans
• Hyaluronan Receptors (genetics, metabolism)
• Lignans (pharmacology)
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Promoter Regions, Genetic
• SOXB1 Transcription Factors (genetics, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transcription, Genetic (drug effects)
• Tumor Burden (drug effects)
• Urinary Bladder Neoplasms (drug therapy, enzymology, genetics, pathology)
• Xenograft Model Antitumor Assays