This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nervi, C. Articles by Cossu, G. Search for Related Content PubMed PubMed Citation Articles by Nervi, C. Articles by Cossu, G.

Inhibition of Histone Deacetylase Activity by Trichostatin A Modulates Gene Expression during Mouse Embryogenesis without Apparent Toxicity¹

Department of Histology and Medical Embryology, University of Rome, 00161 Rome [C. N., U. B., F. F., V. B., G. C.]; Stem Cell Research Institute, Dibit, 20132 Milan [U. B., G. C.]; and European Institute of Oncology, Department of Experimental Oncology, 20141 Milan [P. G. P.], Italy

Remodeling of the chromatin template by inhibition of histone deacetylase (HDAC) activities represents a major goal for transcriptional therapy in neoplastic diseases. Recently, a number of specific and potent HDAC-inhibitors that modulate in vitro cell growth and differentiation have been developed. In this study we analyzed the effect of trichostatin A (TSA), a specific and potent HDAC-inhibitor, on mouse embryos developing in vivo. When administered i.p. to pregnant mice (at a concentration of 0.5–1 mg/kg) at postimplantation stages (embryonic day 8 to embryonic day 10), TSA was not toxic for the mother and did not cause any obvious malformation during somitogenesis or at later stages of development. Treated embryos were born at similar frequency and were indistinguishable from control animals, developed normally, and were fertile. Interestingly, embryos from TSA-treated mice killed during somitogenesis were modestly but consistently larger than control embryos and presented an increased (+2 to +6) number of somites. This correlated with an increased acetylation of histone H4, the number of somites expressing the myogenic factor Myf-5, and the expression of Notch, RAR2, and RARß2 mRNAs. These data indicate that the effects of TSA on transcription: (a) are not toxic for the mother; (b) transiently accelerated growth in mouse embryos without perturbing embryogenesis; and (c) do not result in teratogenesis, at least in rodents. Thus, TSA might represent a nontoxic and effective agent for the transcriptional therapy of neoplasia.

This article has been cited by other articles:

				M.-Y. Kim, E.-J. Ann, J.-Y. Kim, J.-S. Mo, J.-H. Park, S.-Y. Kim, M.-S. Seo, and H.-S. Park Tip60 Histone Acetyltransferase Acts as a Negative Regulator of Notch1 Signaling by Means of Acetylation Mol. Cell. Biol., September 15, 2007; 27(18): 6506 - 6519. [Abstract] [Full Text] [PDF]

				R. V. Kumar, P. C. Mu, V. Ravikumar, and T. Devaki Inhibitory Effects of Histone Deacetylase Inhibitor Depsipeptide on Benzo(a)pyrene- and Cyclophosphamide-Induced Genotoxicity in Swiss Albino Mice International Journal of Toxicology, January 1, 2007; 26(1): 47 - 50. [Abstract] [Full Text] [PDF]

				U. Borello, B. Berarducci, P. Murphy, L. Bajard, V. Buffa, S. Piccolo, M. Buckingham, and G. Cossu The Wnt/{beta}-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis Development, September 15, 2006; 133(18): 3723 - 3732. [Abstract] [Full Text] [PDF]

				G. Cimino, F. Lo-Coco, S. Fenu, L. Travaglini, E. Finolezzi, M. Mancini, M. Nanni, A. Careddu, F. Fazi, F. Padula, et al. Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia. Cancer Res., September 1, 2006; 66(17): 8903 - 8911. [Abstract] [Full Text] [PDF]

				N. K. Mukhopadhyay, E. Weisberg, D. Gilchrist, R. Bueno, D. J. Sugarbaker, and M. T. Jaklitsch Effectiveness of Trichostatin A as a Potential Candidate for Anticancer Therapy in Non-Small-Cell Lung Cancer Ann. Thorac. Surg., March 1, 2006; 81(3): 1034 - 1042. [Abstract] [Full Text] [PDF]

				H. J. Kee, I. S. Sohn, K. I. Nam, J. E. Park, Y. R. Qian, Z. Yin, Y. Ahn, M. H. Jeong, Y.-J. Bang, N. Kim, et al. Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding Circulation, January 3, 2006; 113(1): 51 - 59. [Abstract] [Full Text] [PDF]

				I.-M. Kim, Y. Zhou, S. Ramakrishna, D. E. Hughes, J. Solway, R. H. Costa, and V. V. Kalinichenko Functional Characterization of Evolutionarily Conserved DNA Regions in Forkhead Box F1 Gene Locus J. Biol. Chem., November 11, 2005; 280(45): 37908 - 37916. [Abstract] [Full Text] [PDF]

				C. M. Reilly, N. Mishra, J. M. Miller, D. Joshi, P. Ruiz, V. M. Richon, P. A. Marks, and G. S. Gilkeson Modulation of Renal Disease in MRL/lpr Mice by Suberoylanilide Hydroxamic Acid J. Immunol., September 15, 2004; 173(6): 4171 - 4178. [Abstract] [Full Text] [PDF]

				V. Sartorelli and M. Fulco Molecular and Cellular Determinants of Skeletal Muscle Atrophy and Hypertrophy Sci. Signal., August 3, 2004; 2004(244): re11 - re11. [Abstract] [Full Text] [PDF]

				M. Adachi, Y. Zhang, X. Zhao, T. Minami, R. Kawamura, Y. Hinoda, and K. Imai Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells Clin. Cancer Res., June 1, 2004; 10(11): 3853 - 3862. [Abstract] [Full Text] [PDF]

				A. Gozzini, E. Rovida, P. Dello Sbarba, S. Galimbert, and V. Santini Butyrates, as a Single Drug, Induce Histone Acetylation and Granulocytic Maturation: Possible Selectivity on Core Binding Factor-Acute Myeloid Leukemia Blasts Cancer Res., December 15, 2003; 63(24): 8955 - 8961. [Abstract] [Full Text] [PDF]

				S. Iezzi, G. Cossu, C. Nervi, V. Sartorelli, and P. L. Puri Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases PNAS, May 28, 2002; 99(11): 7757 - 7762. [Abstract] [Full Text] [PDF]

				S. M. Sirchia, M. Ren, R. Pili, E. Sironi, G. Somenzi, R. Ghidoni, S. Toma, G. Nicolo, and N. Sacchi Endogenous Reactivation of the RAR{beta}2 Tumor Suppressor Gene Epigenetically Silenced in Breast Cancer Cancer Res., May 1, 2002; 62(9): 2455 - 2461. [Abstract] [Full Text] [PDF]