在 2006 年，Takahashi and Yamanaka 藉由在細胞內大量表現 Oct4, Sox2, Klf4 及 c-Myc 成功將老鼠胚胎纖維母細胞誘導成具有多能性的幹細胞 (iPS cells)。 而近年研究指出 DNA methyltransferase and histone deacetylase (HDAC) inhibitors 等許多小分子化合物，可有效提升 re-programming 的效率，且有研究指出藉由加入 HDAC inhibitor: Valproic acid (VPA)，可以成功的在只有大量表現 Oct4, Sox2 的情況下，產生多能性的幹細胞。 因此我們的研究集中在 VPA 這個 HDAC 的抑制劑，在我們的研究當中發現 VPA 能夠在C2C12 細胞中提升 Oct4基因的表現並增強 Oct4 1.9k promoter 的活性；在 P19E 細胞中能提升 Sox2 基因的表現，但在 Neuro-2a 和 C2C12 中則不行。 但 Sox2 promoter 的活性卻可以在 P19E 及 C2C12 細胞中被活化。 並發現在大量表現 TR2 及 PPARδ 的情況下，可以增強 VPA 活化 Oct4 promoter 的活性，表示 TR2 及 PPARδ 可能為 VPA 調控 Oct4 promoter 主要的因子。 而 VPA 對 Sox2 promoter 主要的作用位置在-2169~-2111 的區域，此區域具有 Tal1 的 binding site。 利用突變 Tal1 binding site 及 Tal1 knockdown，確實可以大幅降低 Sox2 promoter 對 VPA 的反應，證實 Tal1 對 VPA 活化 Sox2 promoter 的機制扮演重要的角色。 此外處理各種訊息傳遞抑制劑後，發現 LY294002 (Akt inhibitor) 及 rapamycin (mTOR inhibitor) 可以抑制 VPA 活化 Sox2 promoter 的活性，且 VPA 可以活化細胞內的 Akt 和 mTOR，顯示 VPA 可能藉由活化 PI3K/Akt/mTOR pathway 來活化 Sox2 及 Oct4 的 promoter。 而未來將會探討 Tal1 是否會結合在 Sox2 promoter -2169~-2111 的區域，以及瞭解 VPA 經由 PI3K/Akt/mTOR 訊息傳導路徑來影響 Sox2 promoter 活性的機制。

In 2006, Takahashi and Yamanaka reprogrammed mouse embryonic fibroblasts to induced pulripotent stem cells (iPSC) by over-expressing Oct4, Sox2, Klf4 and c-Myc. In recent study, DNA methyltransferase and histone deacetylase (HDAC) inhibitors are found to improve reprogramming efficiency. And they treated valproic acid (VPA), a histone deacetylase inhibitor, to enables reprogramming of primary human fibroblasts with only two factors, Oct4 and Sox2. In this study we found VPA could enhance both the Oct4 1.9k promoter activity and Oct4 expression in C2C12. And VPA could enhance Sox2 expression in P19 cells but not in C2C12 or Neura2A cells. However, Sox2 promoter activity was induced by VPA in both C2C12 and P19 cells. In order to search for major nuclear receptor mediating VPA enhanced Oct4 promoter activation, we found that overexpressing TR2 and PPARδ could enhance the ability of VPA activate Oct4 promoter. VPA response element on Sox2 promoter was localized to the upstream region between -2169 and -2111 bp. Mutation of the Tal1-binding site in this region and Tal1 knockdown largely reduced its VPA response, implying that this binding site plays important role in this response. In addition, we found LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor) could reduce VPA induced Sox2 promoter activity, implying that VPA may activate Oct4 and Sox2 promoters by activating PI3K/Akt/mTOR pathway. In the future, we will define whether Tal1 could directly bind to Sox2 promoter -2169~-2111 region and the mechanism by which VPA activate Sox2 promoter via PI3K/Akt/mTOR signal pathway.

Ambrosetti, D.C., Basilico, C., and Dailey, L. (1997). Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol 17, 6321-6329.
Angelucci, A., Valentini, A., Millimaggi, D., Gravina, G.L., Miano, R., Dolo, V., Vicentini, C., Bologna, M., Federici, G., and Bernardini, S. (2006). Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathways. Anticancer Drugs 17, 1141-1150.
Avilion, A.A., Nicolis, S.K., Pevny, L.H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17, 126-140.
Bernadt, C.T., Nowling, T., and Rizzino, A. (2004). Transcription factor Sox-2 inhibits co-activator stimulated transcription. Mol Reprod Dev 69, 260-267.
Boer, B., Bernadt, C.T., Desler, M., Wilder, P.J., Kopp, J.L., and Rizzino, A. (2006). Differential activity of the FGF-4 enhancer in F9 and P19 embryonal carcinoma cells. J Cell Physiol 208, 97-108.
Boer, B., Kopp, J., Mallanna, S., Desler, M., Chakravarthy, H., Wilder, P.J., Bernadt, C., and Rizzino, A. (2007). Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2:Oct-3/4 target genes. Nucleic Acids Res 35, 1773-1786.
Bradbury, C.A., Khanim, F.L., Hayden, R., Bunce, C.M., White, D.A., Drayson, M.T., Craddock, C., and Turner, B.M. (2005). Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 19, 1751-1759.
Brehm, A., Ohbo, K., and Scholer, H. (1997). The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. Mol Cell Biol 17, 154-162.
Carey, B.W., Markoulaki, S., Hanna, J., Saha, K., Gao, Q., Mitalipova, M., and Jaenisch, R. (2009). Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci U S A 106, 157-162.
Cavallaro, M., Mariani, J., Lancini, C., Latorre, E., Caccia, R., Gullo, F., Valotta, M., DeBiasi, S., Spinardi, L., Ronchi, A., et al. (2008). Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants. Development 135, 541-557.
Cervoni, N., Detich, N., Seo, S.B., Chakravarti, D., and Szyf, M. (2002). The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. J Biol Chem 277, 25026-25031.
Chen, G., Huang, L.D., Jiang, Y.M., and Manji, H.K. (1999). The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72, 1327-1330.
Chen, L., and Khillan, J.S. (2010). A novel signaling by vitamin A/retinol promotes self renewal of mouse embryonic stem cells by activating PI3K/Akt signaling pathway via insulin-like growth factor-1 receptor. Stem Cells 28, 57-63.
Chen, L., and Liu, L. (2009). Current progress and prospects of induced pluripotent stem cells. Sci China C Life Sci 52, 622-636.
Chen, M., Zhang, H., Wu, J., Xu, L., Xu, D., Sun, J., He, Y., Zhou, X., Wang, Z., Wu, L., et al. (2012). Promotion of the induction of cell pluripotency through metabolic remodeling by thyroid hormone triiodothyronine-activated PI3K/AKT signal pathway. Biomaterials 33, 5514-5523.
Chen, Y., Pan, R.L., Zhang, X.L., Shao, J.Z., Xiang, L.X., Dong, X.J., and Zhang, G.R. (2009). Induction of hepatic differentiation of mouse bone marrow stromal stem cells by the histone deacetylase inhibitor VPA. J Cell Mol Med 13, 2582-2592.
Cheng, Y.C., Lin, H., Huang, M.J., Chow, J.M., Lin, S., and Liu, H.E. (2007). Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res 31, 1403-1411.
Chew, J.L., Loh, Y.H., Zhang, W., Chen, X., Tam, W.L., Yeap, L.S., Li, P., Ang, Y.S., Lim, B., Robson, P., et al. (2005). Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol 25, 6031-6046.
Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309, 1369-1373.
Feng, B., Jiang, J., Kraus, P., Ng, J.H., Heng, J.C., Chan, Y.S., Yaw, L.P., Zhang, W., Loh, Y.H., Han, J., et al. (2009). Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 11, 197-203.
Ferri, A.L., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., Ottolenghi, S., Pandolfi, P.P., Sala, M., DeBiasi, S., et al. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131, 3805-3819.
Fuhrmann, G., Chung, A.C., Jackson, K.J., Hummelke, G., Baniahmad, A., Sutter, J., Sylvester, I., Scholer, H.R., and Cooney, A.J. (2001). Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell 1, 377-387.
Gottlicher, M., Minucci, S., Zhu, P., Kramer, O.H., Schimpf, A., Giavara, S., Sleeman, J.P., Lo Coco, F., Nervi, C., Pelicci, P.G., et al. (2001). Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20, 6969-6978.
Grosschedl, R., Giese, K., and Pagel, J. (1994). HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet 10, 94-100.
Guo, Y., Costa, R., Ramsey, H., Starnes, T., Vance, G., Robertson, K., Kelley, M., Reinbold, R., Scholer, H., and Hromas, R. (2002). The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression. Proc Natl Acad Sci U S A 99, 3663-3667.
Gupta, P., Ho, P.C., Huq, M.M., Ha, S.G., Park, S.W., Khan, A.A., Tsai, N.P., and Wei, L.N. (2008). Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression. Proc Natl Acad Sci U S A 105, 11424-11429.
Gurpur, P.B., Liu, J., Burkin, D.J., and Kaufman, S.J. (2009). Valproic acid activates the PI3K/Akt/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy. Am J Pathol 174, 999-1008.
He, L., Liu, H., and Tang, L. (2012). SWI/SNF chromatin remodeling complex: a new cofactor in reprogramming. Stem Cell Rev 8, 128-136.
Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26, 1269-1275.
Jung, G.A., Yoon, J.Y., Moon, B.S., Yang, D.H., Kim, H.Y., Lee, S.H., Bryja, V., Arenas, E., and Choi, K.Y. (2008). Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC Cell Biol 9, 66.
Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771-775.
Kamachi, Y., Uchikawa, M., and Kondoh, H. (2000). Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet 16, 182-187.
Kopp, J.L., Ormsbee, B.D., Desler, M., and Rizzino, A. (2008). Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells 26, 903-911.
Lampen, A., Siehler, S., Ellerbeck, U., Gottlicher, M., and Nau, H. (1999). New molecular bioassays for the estimation of the teratogenic potency of valproic acid derivatives in vitro: activation of the peroxisomal proliferator-activated receptor (PPARdelta). Toxicol Appl Pharmacol 160, 238-249.
Lan, M.J., Yuan, P., Chen, G., and Manji, H.K. (2008). Neuronal peroxisome proliferator-activated receptor gamma signaling: regulation by mood-stabilizer valproate. J Mol Neurosci 35, 225-234.
Lang, K.C., Lin, I.H., Teng, H.F., Huang, Y.C., Li, C.L., Tang, K.T., and Chen, S.L. (2009). Simultaneous overexpression of Oct4 and Nanog abrogates terminal myogenesis. Am J Physiol Cell Physiol 297, C43-54.
Lebreton, S., Carraz, G., Behriel, H., and Meunier, H. (1964). [Pharmacodynamic Properties of 2,2-Dipropylacetic Acid. Iii]. Therapie 19, 457-467.
Lee, M.Y., Lim, H.W., Lee, S.H., and Han, H.J. (2009). Smad, PI3K/Akt, and Wnt-dependent signaling pathways are involved in BMP-4-induced ESC self-renewal. Stem Cells 27, 1858-1868.
Lunke, S., and El-Osta, A. (2009). The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy. J Neurochem 109, 1557-1569.
Marchion, D.C., Bicaku, E., Daud, A.I., Sullivan, D.M., and Munster, P.N. (2005). Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res 65, 3815-3822.
Martirosyan, A., Leonard, S., Shi, X., Griffith, B., Gannett, P., and Strobl, J. (2006). Actions of a histone deacetylase inhibitor NSC3852 (5-nitroso-8-quinolinol) link reactive oxygen species to cell differentiation and apoptosis in MCF-7 human mammary tumor cells. J Pharmacol Exp Ther 317, 546-552.
Mauro, A. (1961). Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 9, 493-495.
McElroy, S.L., Keck, P.E., Jr., Pope, H.G., Jr., and Hudson, J.I. (1989). Valproate in psychiatric disorders: literature review and clinical guidelines. J Clin Psychiatry 50 Suppl, 23-29.
Mesdjian, E., Ciesielski, L., Valli, M., Bruguerolle, B., Jadot, G., Bouyard, P., and Mandel, P. (1982). Sodium valproate: kinetic profile and effects on GABA levels in various brain areas of the rat. Prog Neuropsychopharmacol Biol Psychiatry 6, 223-233.
Meyer, N., and Penn, L.Z. (2008). Reflecting on 25 years with MYC. Nat Rev Cancer 8, 976-990.
Mora, A., Sabio, G., Alonso, J.C., Soler, G., and Centeno, F. (2002). Different dependence of lithium and valproate on PI3K/PKB pathway. Bipolar Disord 4, 195-200.
Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26, 101-106.
Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Scholer, H., and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379-391.
Nishimoto, M., Fukushima, A., Okuda, A., and Muramatsu, M. (1999). The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol 19, 5453-5465.
Niwa, H., Miyazaki, J., and Smith, A.G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-376.
Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.
Palamarchuk, A., Efanov, A., Maximov, V., Aqeilan, R.I., Croce, C.M., and Pekarsky, Y. (2005). Akt phosphorylates Tal1 oncoprotein and inhibits its repressor activity. Cancer Res 65, 4515-4519.
Pan, G.J., Chang, Z.Y., Scholer, H.R., and Pei, D. (2002). Stem cell pluripotency and transcription factor Oct4. Cell Res 12, 321-329.
Pan, T., Li, X., Xie, W., Jankovic, J., and Le, W. (2005). Valproic acid-mediated Hsp70 induction and anti-apoptotic neuroprotection in SH-SY5Y cells. FEBS Lett 579, 6716-6720.
Peltier, J., Conway, A., Keung, A.J., and Schaffer, D.V. (2011). Akt increases sox2 expression in adult hippocampal neural progenitor cells, but increased sox2 does not promote proliferation. Stem Cells Dev 20, 1153-1161.
Pesce, M., and Scholer, H.R. (2000). Oct-4: control of totipotency and germline determination. Mol Reprod Dev 55, 452-457.
Pevny, L., and Placzek, M. (2005). SOX genes and neural progenitor identity. Curr Opin Neurobiol 15, 7-13.
Pikarsky, E., Sharir, H., Ben-Shushan, E., and Bergman, Y. (1994). Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol Cell Biol 14, 1026-1038.
Ralston, A., and Rossant, J. (2005). Genetic regulation of stem cell origins in the mouse embryo. Clin Genet 68, 106-112.
Rizzino, A. (2009). Sox2 and Oct-3/4: a versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells. Wiley Interdiscip Rev Syst Biol Med 1, 228-236.
Rosato, R.R., Almenara, J.A., and Grant, S. (2003). The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 63, 3637-3645.
Rowland, B.D., and Peeper, D.S. (2006). KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6, 11-23.
Scholer, H.R., Ruppert, S., Suzuki, N., Chowdhury, K., and Gruss, P. (1990). New type of POU domain in germ line-specific protein Oct-4. Nature 344, 435-439.
Schoorlemmer, J., van Puijenbroek, A., van Den Eijnden, M., Jonk, L., Pals, C., and Kruijer, W. (1994). Characterization of a negative retinoic acid response element in the murine Oct4 promoter. Mol Cell Biol 14, 1122-1136.
Shan, S.W., Tang, M.K., Chow, P.H., Maroto, M., Cai, D.Q., and Lee, K.K. (2007). Induction of growth arrest and polycomb gene expression by reversine allows C2C12 cells to be reprogrammed to various differentiated cell types. Proteomics 7, 4303-4316.
Smith, K.P., Luong, M.X., and Stein, G.S. (2009). Pluripotency: toward a gold standard for human ES and iPS cells. J Cell Physiol 220, 21-29.
Sommer, C.A., Stadtfeld, M., Murphy, G.J., Hochedlinger, K., Kotton, D.N., and Mostoslavsky, G. (2009). Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 27, 543-549.
Stimson, L., Wood, V., Khan, O., Fotheringham, S., and La Thangue, N.B. (2009). HDAC inhibitor-based therapies and haematological malignancy. Ann Oncol 20, 1293-1302.
Tada, M., Takahama, Y., Abe, K., Nakatsuji, N., and Tada, T. (2001). Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11, 1553-1558.
Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
Teramura, T., Takehara, T., Onodera, Y., Nakagawa, K., Hamanishi, C., and Fukuda, K. (2012). Mechanical stimulation of cyclic tensile strain induces reduction of pluripotent related gene expressions via activation of Rho/ROCK and subsequent decreasing of AKT phosphorylation in human induced pluripotent stem cells. Biochem Biophys Res Commun 417, 836-841.
Terme, J.M., Lhermitte, L., Asnafi, V., and Jalinot, P. (2009). TGF-beta induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation. Blood 113, 6695-6698.
Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147.
Tomioka, M., Nishimoto, M., Miyagi, S., Katayanagi, T., Fukui, N., Niwa, H., Muramatsu, M., and Okuda, A. (2002). Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res 30, 3202-3213.
Wegner, M. (1999). From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27, 1409-1420.
Wegner, M., and Stolt, C.C. (2005). From stem cells to neurons and glia: a Soxist''s view of neural development. Trends Neurosci 28, 583-588.
Werling, U., Siehler, S., Litfin, M., Nau, H., and Gottlicher, M. (2001). Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor delta by valproic acid and its teratogenic derivatives. Mol Pharmacol 59, 1269-1276.
Wernig, M., Meissner, A., Cassady, J.P., and Jaenisch, R. (2008). c-Myc is dispensable for direct reprogramming of mouse fibroblasts. Cell Stem Cell 2, 10-12.
Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J., and Campbell, K.H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810-813.
Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., Hamalainen, R., Cowling, R., Wang, W., Liu, P., Gertsenstein, M., et al. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766-770.
Yang, H.M., Do, H.J., Kim, D.K., Park, J.K., Chang, W.K., Chung, H.M., Choi, S.Y., and Kim, J.H. (2007). Transcriptional regulation of human Oct4 by steroidogenic factor-1. J Cell Biochem 101, 1198-1209.
Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
Zhou, H., Wu, S., Joo, J.Y., Zhu, S., Han, D.W., Lin, T., Trauger, S., Bien, G., Yao, S., Zhu, Y., et al. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381-384.
Ziauddin, M.F., Yeow, W.S., Maxhimer, J.B., Baras, A., Chua, A., Reddy, R.M., Tsai, W., Cole, G.W., Jr., Schrump, D.S., and Nguyen, D.M. (2006). Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation. Neoplasia 8, 446-457.