Research Papers:

Hinokitiol up-regulates miR-494-3p to suppress BMI1 expression and inhibits self-renewal of breast cancer stem/progenitor cells

Shih-Ming Chen, Bing-Yen Wang, Che-Hsin Lee, Hsueh-Te Lee, Jung-Jung Li, Guan-Ci Hong, Yu-Chieh Hung, Peng-Ju Chien, Che-Ying Chang, Li-Sung Hsu _ and Wen-Wei Chang

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Oncotarget. 2017; 8:76057-76068. https://doi.org/10.18632/oncotarget.18648

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Shih-Ming Chen1, Bing-Yen Wang2,3,4,5, Che-Hsin Lee6, Hsueh-Te Lee7, Jung-Jung Li8, Guan-Ci Hong8, Yu-Chieh Hung8, Peng-Ju Chien8, Che-Ying Chang8, Li-Sung Hsu1 and Wen-Wei Chang8,9

1Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

2Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua City, Taiwan

3School of Medicine, Chung Shan Medical University, Taichung, Taiwan

4School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

5Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan

6Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan

7Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei City, Taiwan

8Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan

9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

Correspondence to:

Li-Sung Hsu, email: [email protected]

Wen-Wei Chang, email: [email protected]

Keywords: hinokitiol, miR-494-3p, BMI1, breast cancer, cancer stem cells

Received: March 08, 2017     Accepted: May 14, 2017     Published: June 27, 2017


Hinokitiol (β-thujaplicin) is a tropolone-related compound that has anti-microbe, anti-inflammation, and anti-tumor effects. Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells with tumor initiation, chemoresistant, and metastatic properties and have been considered the important therapeutic target in future cancer therapy. Previous studies reported that hinokitiol exhibits an anti-cancer activity against murine tumor cells through the induction of autophagy. The current research revealed that hinokitiol suppressed the self-renewal capabilities of human breast CSCs (BCSCs) and inhibited the expression of BMI1 at protein level without suppressing its mRNA. Treatment of hinokitiol in mammospheres induced the expression of miR-494-3p and inhibition of miR-494-3p expression in BCSCs. This treatment abolished the suppressive effects of hinokitiol in mammosphere formation and BMI1 expression. BMI1 is a target of miR-494-3p by luciferase-based 3′UTR reporter assay. Overexpression of miR-494-3p in BCSCs caused the down-regulation of BMI1 protein, inhibition of mammosphere forming capability, and suppression of their tumorigenicity. Moreover, miR-494-3p expression was significantly and inversely correlated with patient survival in two independent public database sets. Furthermore, treatment of hinokitiol in vivo suppressed the growth of xenograft human breast tumors as well as the expression of BMI1 and ALDH1A1 in xenograft tumors. In conclusion, these data suggest that hinokitiol targets BCSCs through the miR-494-3p-mediated down-modulation of BMI1 expression.

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