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Published on: May 29, 2015
Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis
Qing Zhang1, Wei Zhao2, Changxiao Ye1
1Department of Urology, Drum Tower Hospital, Medical School of Nanjing University; Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.
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.
Insights
Honokiol inhibits bladder cancer progression by downregulating EZH2 and upregulating miR-143. This study reveals EZH2
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- EZH2 (Enhancer of Zeste Homolog 2) is a histone methyltransferase overexpressed in many cancers.
- Its specific role and regulatory mechanisms in urinary bladder cancer (UBC) remain incompletely understood.
- Understanding EZH2's function in UBC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of EZH2 in human UBC cells.
- To explore the therapeutic potential of honokiol in UBC.
- To elucidate the molecular mechanisms underlying honokiol's effects on UBC, focusing on the EZH2/miR-143 axis.
Main Methods:
- Cell proliferation, survival, stemness, migration, and invasion assays were performed on human UBC cells.
- Expression levels of EZH2, MMP9, CD44, Sox2, and miR-143 were analyzed.
- EZH2 overexpression and miR-143 inhibition were used to assess honokiol's effects.
- In vivo studies involved T24 tumor xenografts in mice treated with honokiol.
- Direct binding of EZH2 to the miR-143 regulatory region was investigated.
Main Results:
- Honokiol inhibited UBC cell proliferation, survival, stemness, migration, and invasion.
- Honokiol downregulated EZH2 expression and upregulated tumor suppressor miR-143.
- EZH2 overexpression or miR-143 inhibition partially reversed honokiol's effects on cell growth and clonogenicity.
- EZH2 was found to directly repress miR-143 transcription.
- Honokiol suppressed tumor growth and stemness in vivo, correlating with EZH2/miR-143 dysregulation.
Conclusions:
- Honokiol exhibits significant anticancer effects in UBC by targeting the EZH2/miR-143 axis.
- EZH2 directly represses miR-143, and honokiol disrupts this interaction.
- Honokiol demonstrates therapeutic potential for bladder cancer treatment by modulating EZH2 and miR-143.
