FR901228, a Potent Antitumor Antibiotic, Is a Novel Histone Deacetylase Inhibitor

Nakajima, Hidenori; Kim, Young Bae; Terano, Hiroshi; Yoshida, Minoru; Horinouchi, Sueharu

doi:10.1006/excr.1998.4027

Cited by 461 publications

(320 citation statements)

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“…By contrast, DEP is a natural tetrapeptide HDAC inhibitor that is currently in phase I and II clinical trials for treating hematological malignancies and solid tumors (Piekarz et al, 2001;Marshall et al, 2002;Sandor et al, 2002;Piekarz and Bates, 2004;Byrd et al, 2005). DEP inhibits all the known Class I and Class II HDAC enzymes (Nakajima et al, 1998). DEP is typically used at a concentration of 5 nM, but even at 10-fold lower levels it caused a dramatic accumulation of acetylated histones (Figure 2a and b).…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

et al. 2006

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“…In fact, oxam¯atin showed antitumor activity against B16 melanoma. FR901228, which was recently identi®ed as a new type of HDAC inhibitor (Nakajima et al, 1998), is remarkably active in vivo against experimental tumors (Ueda et al, 1994a) and is now under clinical investigation (Phase I) in the National Cancer Institute (Bethesda, MD, USA). It is therefore useful in cancer chemotherapy to explore the possibility of oxam¯atin and other HDAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…E ects of oxam¯atin on the integrated CMV promoter activity n-Butyrate and TSA are known to modulate transcriptional regulatory elements, including viral elements such as retroviral long terminal repeats (Chen et al, 1997), simian virus (Goldberg et al, 1992;Nakajima et al, 1998) and cytomegalovirus promoters (Dion et al, 1997;Tanaka et al, 1991). To analyse the e ect of oxam¯atin on the activity of modulating the integrated viral promoters, we determined the luciferase reporter activity in NIH3T3 cells stably transfected with pBCLuc.…”

Section: E Ects Of Oxam¯atin On the Cell Morphology Of Hela Cellsmentioning

confidence: 99%

“…All known HDAC inhibitors in addition to oxam¯atin induce G1 cell cycle arrest and morphological changes in various cell lines (Fallon and Cox, 1979; Kijima et , 1993;Nakajima et al, 1998;Yoshida and Beppu, 1988). Recent studies have shown that HAT acts as the transcriptional coactivator (Bannister and Kouzarides, 1996;Brownell et al, 1996;Mizzen et al, 1996;Ogryzko et al, 1996;Yang et al, 1996b) whereas HDAC behaves as the corepressor Hassig et al, 1997;Kadosh and Struhl, 1997;Laherty et al, 1997;Nagy et al, 1997;Yang et al, 1996a).…”

Section: E Ects Of Oxam¯atin On Endogenous Gene Expressionmentioning

confidence: 99%

“…For instance, trichostatin A (TSA), trapoxin, and FR901228 revert the cell morphology of v-sis and v-ras-transformed cells to apparently normal ones (Futamura et al, 1995;Itazaki et al, 1990;Sugita et al, 1992;Ueda et al, 1994b). Histone deacetylases (HDAC) were shown to be the molecular targets of these agents (Kijima et al, 1993;Nakajima et al, 1998;Yoshida et al, 1990). Human HDAC (HDAC1) was puri®ed and cloned by using trapoxin-based a nity matrix (Taunton et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

et al. 1999

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Oxam¯atin [(2E) -5 -[3 -[(phenylsufonyl) amino] phenyl]-pent-2-en-4-ynohydroxamic acid] induces transcriptional activation of junD and morphological reversion in various NIH3T3-derived transformed cell lines. We found that oxam¯atin showed in vitro antiproliferative activity against various mouse and human tumor cell lines with drastic changes in the cell morphology and in vivo antitumor activity against B16 melanoma. Oxam¯atin caused an elongated cell shape with ®lamentous protrusions as well as arrest of the cell cycle at the G1 phase in HeLa cells. These phenotypic changes of HeLa cells were apparently similar to those by trichostatin A (TSA), a speci®c inhibitor of histone deacetylase (HDAC). The e ect of oxam¯atin on the transcriptional activity of the cytomegalovirus (CMV) promoter was examined and compared with known HDAC inhibitors, TSA, sodium n-butyrate, and FR901228. Oxam¯atin as well as all these inhibitors greatly enhanced the transcriptional activity of the CMV promoter in a dose-dependent manner. Oxam¯atin, like TSA, inhibited intracellular HDAC activity, as a result of which marked amounts of acetylated histone species accumulated. Finally, e ects on expression of several endogenous genes involved in cell morphology and cell cycle control in HeLa cells were analysed. Expression of gelsolin, cyclin E and Cdk inhibitors including p21 WAF1/Cip1 was highly augmented, while that of cyclin A and cyclin D1 was decreased by oxam¯atin. These results suggest that changes in the expression pattern of the genes regulating cell morphology and the cell cycle due to histone hyperacetylation are responsible for the antitumor activity, the morphological change and the cell cycle arrest induced by oxam¯atin.

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Regulation and regulatory parameters of histone modifications

Davie

Chadee

1998

J. Cell. Biochem.

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Histone acetylation and phosphorylation destablizes nucleosome and chromatin structure. Relaxation of the chromatin fiber facilitates transcription. Coactivator complexes with histone acetyltransferase activity are recruited by transcription factors bound to enhancers or promoters. The recruited histone acetyltransferases may acetylate histone or nonhistone chromosomal proteins, resulting in the relaxation of chromatin structure. Alternatively, repressors recruit corepressor complexes with histone deacetylase activity, leading to condensation of chromatin.This review highlights the recent advances made in our understanding of the roles of histone acetyltransferases, histone deacetylases, histone kinases, and protein phosphatases in transcriptional activation and repression. Exciting reports revealing mechanistic connections between histone modifying activities and the RNA polymerase II machinery, the coupling of histone deacetylation and DNA methylation, the possible involvement of histone deacetylases in the organization of nuclear DNA, and the role of chromatin modulators in oncogenesis are discussed. J. Cell. Biochem. Suppls. 30/31:203-213, 1998. © 1998 Wiley-Liss, Inc.

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FR901228, a Potent Antitumor Antibiotic, Is a Novel Histone Deacetylase Inhibitor

Cited by 461 publications

References 59 publications

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Regulation and regulatory parameters of histone modifications

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