miR-326-Histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs [Molecular Bases of Disease]

August 19th, 2014 by Kim, Y., Kim, H., Park, H., Park, D., Lee, H., Lee, Y. S., Choe, J., Kim, Y. M., Jeoung, D.

Histone modification has been known to be associated with multidrug-resistance phenotype. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression level of histone deacetylase-3 (HDAC3), among HDAC(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 while miR-326 inhibitor increased the apoptotic effect of anti-cancer drugs. miR-326 enhanced the invasion and migration potential of cancer cells. miR-326 inhibitor negatively regulated the tumorigenic, metastatic and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed 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 CAGE, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and miR-326 acted upstream of CAGE. Thus, we show that miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.
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