• BMB Reports
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• v.51 no.5
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• pp.211-218
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• 2018

Chromatin is an intelligent building block that can express either external or internal needs through structural changes. To date, three methods to change chromatin structure and regulate gene expression have been well-documented: histone modification, histone exchange, and ATP-dependent chromatin remodeling. Recently, a growing body of literature has suggested that histone tail cleavage is related to various cellular processes including stem cell differentiation, osteoclast differentiation, granulocyte differentiation, mammary gland differentiation, viral infection, aging, and yeast sporulation. Although the underlying mechanisms suggesting how histone cleavage affects gene expression in view of chromatin structure are only beginning to be understood, it is clear that this process is a novel transcriptional epigenetic mechanism involving chromatin dynamics. In this review, we describe the functional properties of the known histone tail cleavage with its proteolytic enzymes, discuss how histone cleavage impacts gene expression, and present future directions for this area of study.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.115-122
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• 2024

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

• Journal of Microbiology and Biotechnology
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• v.25 no.9
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• pp.1578-1582
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• 2015

Granzyme A (GzmA) was identified as a cytotoxic T lymphocyte protease protein expressed in the nucleus. A number of nuclear proteins are well known as GzmA substrates, and GzmA is related with caspase-independent apoptosis. Histones H1, H2B, and H3 were identified as GzmA substrates through in vitro experiment with purified nucleosome. Here, we demonstrated that histone H3 was cleaved by GzmA in vivo during staurosporine-induced cell death. Moreover, histone H3 cleavage was blocked by the GzmA inhibitor nafamostat mesylate and by GzmA knockdown using siRNA. Taken together, we verified that histone H3 is a real substrate for GzmA in vivo in the Raji cells treated by staurosporin.

• BMB Reports
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• v.49 no.10
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• pp.560-565
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• 2016

Granzyme A (GzmA) was first identified as a cytotoxic T lymphocyte protease protein with limited tissue expression. A number of cellular proteins are known to be cleaved by GzmA, and its function is to induce apoptosis. Histones H1, H2B, and H3 were identified as GzmA substrates during apoptotic cell death. Here, we demonstrated that histone H4 was cleaved by GzmA during staurosporine-induced cell death; however, in the presence of caspase inhibitors, staurosporine-treated Raji cells underwent necroptosis instead of apoptosis. Furthermore, histone H4 cleavage was blocked by the GzmA inhibitor nafamostat mesylate and by GzmA knockdown using siRNA. These results suggest that histone H4 is a novel substrate for GzmA in staurosporine-induced cells.

• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.423-434
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• 2019

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the growth and survival of cancer cells. HSP90 inhibitors mainly bind to the ATP binding site of HSP90 and inhibit HSP90 activity, and these inhibitors can be distinguished as ansamycin and non-ansamycin depending on the structure. In addition, the histone deacetylase inhibitors inhibit the activity of HSP90 through acetylation of HSP90. These HSP90 inhibitors have undergone or are undergoing clinical trials for the treatment of cancer. On the other hand, recent studies have reported that various reagents induce cleavage of HSP90, resulting in reduced HSP90 client proteins and growth suppression in cancer cells. Cleavage of HSP90 can be divided into enzymatic cleavage and non-enzymatic cleavage. Therefore, reagents inducing cleavage of HSP90 can be classified as another class of HSP90 inhibitors. We discuss that the cleavage of HSP90 can be another mechanism in the cancer treatment by HSP90 inhibition.

• Proceedings of the KSAR Conference
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• 2004.06a
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• pp.189-189
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• 2004

Histone acetylation as epigenetic marker plays a critical role in gene expression through the interaction of nucleosomes with DNA, modulating the efficiency which RNA-polymerase can interact with promotors to initiate transcription. After fertilization, highly acetylated chromatin takes place and maintain during 1cell stages. The hyperacetylation may lead minor genome activation for survival and cleavage, and then may affect embryonic genome activation and development to balstocyst. (omitted)

• Reproductive and Developmental Biology
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• v.38 no.4
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• pp.147-158
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• 2014

Differentiated nuclei can experimentally be returned to an undifferentiated embryonic status after nuclear transfer (NT) to unfertilized metaphase II (MII) oocytes. Nuclear reprogramming is triggered immediately after somatic cell nucleus transfer (SCNT) into recipient cytoplasm and this period is regarded as a key stage for optimizing reprogramming. In a recent study (Dai et al., 2010), use of m-carboxycinnamic acid bishydroxamide (CBHA) as a histone deacetylase inhibitor during the in vitro early culture of murine cloned embryos modifies the acetylation status of somatic nuclei and increases the developmental competence of SCNT embryos. Thus, we examined the effects of CBHA treatment on the in vitro preimplantation development of porcine SCNT embryos and on the acetylated status of histone H3K9 on cloned embryos at the zygote stage. We performed the three groups SCNT: SCNT (NT), CBHA treatment at the porcine fetus fibroblast cells (PFFs) used as donor cells prior to SCNT (CBHA-C) and CBHA treatment at the porcine SCNT embryos during the in vitro early culture after oocyte activation (CBHA-Z). The PFFs were treated with a $15{\mu}M$ of CBHA (8 h) for the early culture and the porcine cloned embryos were treated with a $100{\mu}M$ concentration of CBHA during the in vitro early culture (10 h). Cleavage rates and development to the blastocyst stage were assessed. No significant difference was observed the cleavage rate among the groups (82.6%, 76.4% and 82.2%, respectively). However, the development competence to the blastocyst stage was significantly increased in CBHA-Z embryos (22.7%) as compared to SCNT and CBHA-C embryos (8.6% and 4.1%)(p<0.05). Total cell numbers and viable cell numbers at the blastocyst stage of porcine SCNT embryos were increased in CBHA-Z embryos as compared to those in CBHA-C embryos (p<0.05). Signal level of histone acetylation (H3K9ac) at the zygote stage of SCNT was increased in CBHA-Z embryos as compared to SCNT and CBHA-C embryos. The results of the present study suggested that treatment with CBHA during the in vitro early culture (10 h) had significantly increased the developmental competence and histone acetylation level at the zygote stage.

• Korean Journal of Microbiology
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• v.53 no.4
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• pp.286-291
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• 2017

In eukaryotic cells, histone modification is an important mechanism to regulate the chromatin structure. The methylation of the fourth lysine on histone H3 (H3K4) by Set1 complex is one of the various well-known histone modifications. Set1 complex has seven subunits including Swd2, which is known to be important for H2B ubiquitination dependent on H3K4 methylation. Swd2 was reported to regulate Set1's methyltransferase activity by binding to near RNA recognition motif (RRM) domain of Set1 and to act as a component of CPF (Cleavage and Polyadenylation Factors) complex involved in RNA 3' end processing. According to the recent reports, two functions of Swd2 work independently of each other and the lethality of Swd2 knockout strain was known to be caused by its function as a component of CPF complex. In this study, we found that Swd2 could influence the Set1's stability as well as histone methyltransferase activity through the association with RRM domain of Set1. Also, we found that ${\Delta}swd2$ mutant bearing truncated-Set1, which cannot interact with Swd2, lost its lethality and grew normally. These results suggest that the dual functions of Swd2 in H3K4 methylation and RNA 3' end processing are not independent in Saccharomyces cerevisiae.

• Toxicological Research
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• v.19 no.3
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• pp.197-203
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• 2003

Apicidin, a histone-deacetylase inhibitor, has been successfully used to inhibit the growth of cancer cells. In this study, the apoptotic potential and mechanistic insights of apicidin were investigated in human myeloid leukemia U937 cells. Treatment of U937 cells with apicidin resulted in a decrease of cell viability with apoptotic characteristics, including chromatin condensation and ladder-pattern fragmentation of genomic DNA. Apicidin converted the procaspase-3 protease to catalytically active effector protease, resulting in subsequent cleavage of poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, apicidin induced the activation of caspase-9 protease and the cytosolic release of mitochondrial cytochrome c with mitochon-drial membrane potential transition. Moreover, apicidin transiently increased the expression of Fas and Fas ligand proteins. Taken together, the results suggest that apicidin induces apoptosis of U937 cells through activation of intrinsic caspase cascades and Fas/FasL system with mitochondrial dysfunction.

• Biomolecules & Therapeutics
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• v.17 no.1
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• pp.17-24
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• 2009

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents that inhibit cancer cell growth in vitro and in vivo. Previous report has shown that apicidin inhibited SK-OV-3 cells proliferation and down-regulation of cyclin B1 and CDK1, and up-regulation of $p21^{WAF1}$ and p27. However, the mechanism of apicidin-mediated apoptotic cell death is not clearly understood. For this study, we investigated the mechanism of apoptotic pathway induced by apicidin in human ovarian cancer cell. We found that SK-OV-3 cells treated with apicidin caused an increase in the percentage of cells in the G2/M phase, which preceded apoptosis characterized by the appearance of cells with sub-G1 population. To further investigate the mechanism of apoptosis induction by apicidin, we measured TUNEL assay, poly-ADP ribose polymerase (PARP) cleavage, and caspase activity in SK-OV-3 cells treated with apicidin for 48 h. Apicidin significantly enhanced apoptosis as measured by TUNEL positive apoptotic cells, PARP cleavage, and increased Bax/Bcl-2 ratio. Induction of apoptosis was confirmed by the release of cytochrome c to cytosol. Our data suggest that apicidin-induced apoptosis in SK-OV-3 cells was accompanied by caspase-3 activation and the increase in Bax/Bcl-2 ratio. These data suggest that apicidin may be effective in the treatment of ovarian cancer through activation of intrinsic apoptotic pathway.