miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3

Kim, Youngmi,Kim, Hyuna,Park, Deokbum,Jeoung, Dooil Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.6

We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drug-resistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anti-cancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3'-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3

김영미,김현아,박덕범,정두일 한국분자세포생물학회 2015 Molecules and cells Vol.38 No.6

We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drugresistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anticancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anticancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR- 335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.

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

Kim, Youngmi,Kim, Hyuna,Park, Hyunmi,Park, Deokbum,Lee, Hansoo,Lee, Yun Sil,Choe, Jongseon,Kim, Young Myeong,Jeoung, Dooil American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.40

<P>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 <I>in vitro</I> and <I>in vivo</I>. TargetScan analysis predicted <I>miR-326</I> as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and <I>miR-326. miR-326</I> decreased the apoptotic effect of anti-cancer drugs, and the <I>miR-326</I> inhibitor increased the apoptotic effect of anti-cancer drugs. <I>miR-326</I> enhanced the invasion and migration potential of cancer cells. The <I>miR-326</I> 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 <I>miR-200b</I>, <I>miR-217</I>, and <I>miR-335. miR-200b</I>, <I>miR-217</I>, and <I>miR-335</I> negatively regulated the expression of <I>miR-326</I> and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted <I>miR-200b</I> and <I>miR-217</I> as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and <I>miR-326</I> 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.</P>

한방항암제의 세계화를 위한 전략

박경훈,이중엽,최현진,김선지,박병주 한국보건의료기술평가학회 2017 보건의료기술평가 Vol.5 No.1

Cancer is the leading cause of death worldwide and the most important cause of death in Korea. Many researches have been conducted for developing effective and safe anti-cancer drugs worldwide. Korean government recently declared to make traditional herbal medicine globally recognized and began to invest not a small budget for developing new promising herbal anti-cancer drugs. The pur- pose of this study is to investigate the scientific evidence of current Korean herbal medicines to be able to enter the world market through the studies of NEXIA. NEXIA (Rhus verniciflua Stokes), anti- cancer drug from traditional herbal medicine in Korea, has been used by Korean medicine physician legally without Ministry of Drug and Food Safety’s formal approval through a new drug approval system. We have found the studies on the NEXIA have not enough scientific evidence on safety and effectiveness due to lack of internal validity of the studies. In order to make our traditional herbal an- ti-cancer drugs successfully enter the world market, we have to establish effective system for evaluat- ing them through the world-widely recognized system such as clinical trial system of cancer drugs run by the U.S Food and Drug Administration. It should be prerequisite to establish sound evaluation system for safety and effectiveness of Korean herbal anti-cancer drugs for developing globally accept- able Korean herbal anti-cancer drugs.

Role of HDAC3-miRNA-CAGE Network in Anti-Cancer Drug-Resistance

Kwon, Yoojung,Kim, Youngmi,Jung, Hyun Suk,Jeoung, Dooil MDPI 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.1

<P>Histone modification is associated with resistance to anti-cancer drugs. Epigenetic modifications of histones can regulate resistance to anti-cancer drugs. It has been reported that histone deacetylase 3 (HDAC3) regulates responses to anti-cancer drugs, angiogenic potential, and tumorigenic potential of cancer cells in association with cancer-associated genes (CAGE), and in particular, a cancer/testis antigen gene. In this paper, we report the roles of microRNAs that regulate the expression of HDAC3 and CAGE involved in resistance to anti-cancer drugs and associated mechanisms. In this review, roles of HDAC3-miRNAs-CAGE molecular networks in resistance to anti-cancer drugs, and the relevance of HDAC3 as a target for developing anti-cancer drugs are discussed.</P>

Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs

Kim, Youngmi,Kim, Hyuna,Jeoung, Dooil Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.8

We investigated the role of HDAC3 in anti-cancer drug-resistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The down-regulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin ${\beta}3$ was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin ${\beta}3$ and HDAC6. HDAC6 showed an interaction with tubulin ${\beta}3$. HDAC3 had a negative regulatory role in the expression of tubulin ${\beta}3$ and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin ${\beta}3$, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin ${\beta}3$ did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin ${\beta}3$ conferred sensitivity to anti-cancer drugs. Our results showed that tubulin ${\beta}3$ serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin ${\beta}$ axis can be employed for the development of anti-cancer drugs.

Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule-Targeting Drugs

김영미,정두일,김현아 한국분자세포생물학회 2015 Molecules and cells Vol.38 No.8

We investigated the role of HDAC3 in anti-cancer drugresistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The downregulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin β3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin β3 and HDAC6. HDAC6 showed an interaction with tubulin β3. HDAC3 had a negative regulatory role in the expression of tubulin β3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin β3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin β3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin β3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin β3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin β axis can be employed for the development of anti-cancer drugs.

Biotransformation, a Promising Technology for Anti-cancer Drug Development

Gao, Fei,Zhang, Jin-Ming,Wang, Zhan-Guo,Peng, Wei,Hu, Hui-Ling,Fu, Chao-Mei Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10

With the high morbidity and mortality caused by cancer, finding new and more effective anti-cancer drugs is very urgent. In current research, biotransformation plays a vital role in the research and development of cancer drugs and has obtained some achievements. In this review, we have summarized four applications as follows: to exploit novel anti-cancer drugs, to improve existing anti-cancer drugs, to broaden limited anti-cancer drug resources and to investigate correlative mechanisms. Three different groups of important anti-cancer compounds were assessed to clarify the current practical applications of biotransformation in the development of anti-cancer drugs.

DDX53 Promotes Cancer Stem Cell-Like Properties and Autophagy

Kim, Hyuna,Kim, Youngmi,Jeoung, Dooil Korean Society for Molecular and Cellular Biology 2017 Molecules and cells Vol.40 No.1

Although cancer/testis antigen DDX53 confers anti-cancer drug-resistance, the effect of DDX53 on cancer stem cell-like properties and autophagy remains unknown. MDA-MB-231 ($CD133^+$) cells showed higher expression of DDX53, SOX-2, NANOG and MDR1 than MDA-MB-231 ($CD133^-$). DDX53 increased in vitro self-renewal activity of MCF-7 while decreasing expression of DDX53 by siRNA lowered in vitro self-renewal activity of MDA-MB-231. DDX53 showed an interaction with EGFR and binding to the promoter sequences of EGFR. DDX53 induced resistance to anti-cancer drugs in MCF-7 cells while decreased expression of DDX53 by siRNA increased the sensitivity of MDA-MB-231 to anti-cancer drugs. Negative regulators of DDX53, such as miR-200b and miR-217, increased the sensitivity of MDA-MB-231 to anti-cancer drugs. MDA-MB-231 showed higher expression of autophagy marker proteins such as ATG-5, $pBeclin1^{Ser15}$ and LC-3I/II compared with MCF-7. DDX53 regulated the expression of marker proteins of autophagy in MCF-7 and MDA-MB-231 cells. miR-200b and miR-217 negatively regulated the expression of autophagy marker proteins. Chromatin immunoprecipitation assays showed the direct regulation of ATG-5. The decreased expression of ATG-5 by siRNA increased the sensitivity to anti-cancer drugs in MDA-MB-231 cells. In conclusion, DDX53 promotes stem cell-like properties, autophagy, and confers resistance to anti-cancer drugs in breast cancer cells.

DDX53 Promotes Cancer Stem Cell-Like Properties and Autophagy

김현아,김영미,정두일 한국분자세포생물학회 2017 Molecules and cells Vol.40 No.1

Although cancer/testis antigen DDX53 confers anti-cancer drug-resistance, the effect of DDX53 on cancer stem cell-like properties and autophagy remains unknown. MDA-MB-231 (CD133+) cells showed higher expression of DDX53, SOX-2, NANOG and MDR1 than MDA-MB-231 (CD133-). DDX53 increased in vitro self-renewal activity of MCF-7 while decreasing expression of DDX53 by siRNA lowered in vitro self-renewal activity of MDA-MB-231. DDX53 showed an interaction with EGFR and binding to the promoter sequences of EGFR. DDX53 induced resistance to anti-cancer drugs in MCF-7 cells while decreased expression of DDX53 by siRNA increased the sensitivity of MDA-MB-231 to anti-cancer drugs. Negative regulators of DDX53, such as miR-200b and miR-217, increased the sensitivity of MDA-MB-231 to anti-cancer drugs. MDA-MB-231 showed higher expression of autophagy marker proteins such as ATG-5, pBeclin1Ser15 and LC-3I/II compared with MCF-7. DDX53 regulated the expression of mark-er proteins of autophagy in MCF-7 and MDA-MB-231 cells. miR-200b and miR-217 negatively regulated the expression of autophagy marker proteins. Chromatin immunoprecipitation assays showed the direct regulation of ATG-5. The decreased expression of ATG-5 by siRNA increased the sensitivity to anti-cancer drugs in MDA-MB-231 cells. In conclusion, DDX53 promotes stem cell-like properties, autophagy, and confers resistance to anti-cancer drugs in breast cancer cells.