miR-326-Histone Deacetylase-3 Feedback Loop Regulates the Invasion and Tumorigenic and Angiogenic Response to Anti-cancer Drugs

被引：40

作者：

Kim, Youngmi ^{[1
]}

Kim, Hyuna ^{[1
]}

Park, Hyunmi ^{[1
]}

Park, Deokbum ^{[1
]}

Lee, Hansoo ^{[2
]}

Lee, Yun Sil ^{[4
]}

Choe, Jongseon ^{[3
]}

Kim, Young Myeong ^{[3
]}

Jeoung, Dooil ^{[1
]}

机构：

[1] Kangwon Natl Univ, Dept Biochem, Coll Nat Sci, Chunchon 200701, South Korea

[2] Kangwon Natl Univ, Dept Biol Sci, Coll Nat Sci, Chunchon 200701, South Korea

[3] Kangwon Natl Univ, Grad Sch Med, Chunchon 200701, South Korea

[4] Ewha Womans Univ, Coll Pharm, Seoul 120750, South Korea

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 40期

基金：

新加坡国家研究基金会;

关键词：

Angiogenesis; Gene Expression; Histone Deacetylase 3 (HDAC3); MicroRNA (miRNA); Tumor Metastases; Anti-cancer Drug Resistance; Feedback Loop; miR-326; CANCER/TESTIS ANTIGEN CAGE; HISTONE DEACETYLASE; CELL-PROLIFERATION; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; GENE-EXPRESSION; LUNG-CANCER; HDAC3; RESISTANCE; PACLITAXEL;

D O I：

10.1074/jbc.M114.578229

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs in vitro and in vivo. TargetScan analysis predicted miR-326 as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and miR-326. miR-326 decreased the apoptotic effect of anti-cancer drugs, and the miR-326 inhibitor increased the apoptotic effect of anti-cancer drugs. miR-326 enhanced the invasion and migration potential of cancer cells. The miR-326 inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as miR-200b, miR-217, and miR-335. miR-200b, miR-217, and miR-335 negatively regulated the expression of miR-326 and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted miR-200b and miR-217 as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and miR-326 acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.

引用

页码：28019 / 28039

页数：21

共 49 条

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Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer [J].