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

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// Shih-Ming Chen 1 , Bing-Yen Wang 2, 3, 4, 5 , Che-Hsin Lee 6 , Hsueh-Te Lee 7 , Jung-Jung Li 8 , Guan-Ci Hong 8 , Yu-Chieh Hung 8 , Peng-Ju Chien 8 , Che-Ying Chang 8 , Li-Sung Hsu 1 and Wen-Wei Chang 8, 9 1 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan 2 Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua City, Taiwan 3 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 4 School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan 6 Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan 7 Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei City, Taiwan 8 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan 9 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan Correspondence to: Li-Sung Hsu, email: lsh316@csmu.edu.tw Wen-Wei Chang, email: changww@csmu.edu.tw Keywords: hinokitiol, miR-494-3p, BMI1, breast cancer, cancer stem cells Received: March 08, 2017 Accepted: May 14, 2017 Published: June 27, 2017 ABSTRACT 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.