miR-326-histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs.

Abstract

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.

• Authors: Youngmi Kim, Hyuna Kim, Hyunmi Park, Deokbum Park, Hansoo Lee, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Dooil Jeoung
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 40 Pg. 28019-39 (Oct 03 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25138213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antineoplastic Agents
• MIRN326 microRNA, human
• MicroRNAs
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinogenesis (drug effects, genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Feedback, Physiological (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylases (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasms (enzymology, genetics, pathology)
• Neovascularization, Pathologic (drug therapy, enzymology, genetics, pathology)