Transcriptional suppression of Dicer by HOXB-AS3/EZH2 complex dictates sorafenib resistance and cancer stemness

被引：12
作者：
Tseng, Chi-Feng [1 ,2 ,3 ]
Chen, Li-Tzong [3 ,4 ,5 ]
Wang, Horng-Dar [2 ]
Liu, Yi-Hong [2 ,3 ]
Shiah, Shine-Gwo [3 ,6 ]
机构：
[1] NTHU & NH RI, Grad Program Biotechnol Med, Zhunan, Taiwan
[2] Natl Tsing Hua Univ, Inst Biotechnol, Hsinchu, Taiwan
[3] Natl Inst Canc Res, Natl Hlth Res Inst, 35 Keyan Rd, Zhunan 35053, Miaoli County, Taiwan
[4] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Dept Oncol, Tainan, Taiwan
[5] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Internal Med, Kaohsiung, Taiwan
[6] Kaohsiung Med Univ, Program Environm & Occupat Med, Kaohsiung, Taiwan
来源：
CANCER SCIENCE | 2022年 / 113卷 / 05期
关键词：
Dicer; EZH2; HOXB-AS3; liver cancer; sorafenib resistance; LONG NONCODING RNA; TUMOR-SUPPRESSOR; EXPRESSION; EZH2; POLYCOMB; REPRESSION; INHIBITION; SURVIVAL; PROTEIN; HOTAIR;
D O I：
10.1111/cas.15319
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Sorafenib is a multikinase inhibitor for the standard treatment of advanced liver cancer patients. However, acquired resistance to sorafenib is responsible for a poor prognosis. Therefore, uncovering the molecular mechanisms underlying sorafenib sensitization can provide biomarkers for sorafenib treatment and improve sorafenib activity in a precise medication. Here, we report that epigenetic suppression of Dicer by the HOXB-AS3/EZH2 complex is responsible for sorafenib resistance. We observed that Dicer expression is inversely correlated with EZH2 levels, HOXB-AS3 expression, sorafenib resistance, and cancer stem cell properties in liver cancer patients. Furthermore, ectopic expression of Dicer induced liver cancer cells resensitization to sorafenib. Mechanistically, we found HOXB-AS3 physically interacts with EZH2 and recruits EZH2 to the Dicer promoter, resulting in epigenetic suppression of Dicer expression. These findings reveal that HOXB-AS3/EZH2 complex-mediated Dicer suppression plays an important role in sorafenib resistance and cancer stemness and provide potential therapeutic strategies for diagnosing and treating liver cancer patients.
引用
收藏
页码：1601 / 1612
页数：12
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