Histone Acetylation Enhances The Transcriptional Activation Of Mda-7 Induced By Sp1

Mda-7/IL-24 (melanoma differentiation associated gene/Interleukin-24) was first discovered as a cytokine gene that can be induced by PHA or LPS in human peripheral blood mononuclear cells (PBMC). The mda-7 gene is located in the genomic cluster of IL-10-related genes, and it functions as a pro-Th1 cytokine. Ectopic expression of mda-7 induced by adenovirus (Ad.mda-7) increases IL-6 and IFN-γmRNA expression, and triggeres the secretion of IFN-γand IL-6 from melanoma cells. In addition, mda-7 is a tumor suppressor gene, which constitutively expresses in normal melanocytes to maintain the normal physiology function of the cells, and induces cell terminal differentiation; but its expression gradually fades with the progression of melanoma and is almost undetectable at the metastatic stage. Ad-mda7 can selectively induce apoptosis in a broad range of tumor cells while with few adverse effects to normal cells. Furthermore, there was evidence that the absence of mda-7 expression in cancer cells was not a result of gene mutation, since no chromatin structural rearrangements were observed in cancer and normal cells. The fact that mda-7 can be induced in cancer cells suggests that there may be other regulation mechanisms that control the expression of mda-7. Presumably, epigenetic changes such as histone acetylation modification may play a role in transcription regulation of mda-7; however, this has not been elucidated.We show in this study that the expression of mda-7 was up-regulated by histone deacetylase (HDAC) inhibitors TSA and NaBu, while it was down-regulated by HDAC4. We also found that the histone acetylation level and the binding of transcriptional factor Sp1 on the mad-7 promoter were reduced after HDAC4 treatment. Moreover, HDAC inhibitor TSA induced histone hyperacetylation and stimulated Sp1 binding to mda-7 promoter, which in turn enhanced the expression of mda-7. Therefore, we conclude that histone acetylation modification is an insignificant factor in regulation of mda-7, and the transcription factor Sp1 participates in this process.