Melanoma differentiation-associated gene/interleukin-24(mda-7/IL-24)is a cytokine that can activate monocytes and T helper 2 cells.The expression of mda-7/IL-24 gradually fades with the progression of melanoma,and it is undetectable at the metastatic stage.Ectopic expression of mda-7/IL-24 selectively suppresses growth and induces apoptosis in cancer cells with little harm to normal cells.However,the transcriptional regulation of the mda-7/IL-24 gene has not been extensively studied.In this study,we show that the expression of mda-7/IL-24 was upregulated by the histone deacetylase(HDAC)inhibitors trichostatin A(TSA)and sodium butyrate(NaBu),whereas it was downregulated by HDAC4.We also found that the histone acetylation level and the binding of the transcriptional factor Sp1 to the mad-7 promoter were reduced upon HDAC4 treatment.Moreover,the HDAC inhibitor TSA induced histone hyperacetylation and stimulated Sp1 binding to the mda-7/IL-24 promoter,which in turn enhanced the expression of mda-7/IL-24.Therefore,we conclude that histone acetylation modification plays an important role in the regulation of mda-7/IL-24 and that the transcription factor Sp1 participates in this process.
Lina PanHong PanHao JiangJuan DuXiuli WangBaiqu HuangJun Lu
The human pituitary tumor transforming gene (hPTTG) serves as a marker for malignancy grading in several cancers. hPTTG is involved in multiple cellular pathways including cell transformation, apoptosis, DNA repair, genomic instability, mitotic control and angiogenesis induction. However, the molecular mechanisms underlying hPTTG regulation have not been fully explored. In this study, we found that overexpression of histone acetyltransferase (HAT) p300 upregulated hPTTG at the levels of promoter activity, mRNA and pro- tein expression. Moreover, the HAT activity of p300 was critical for its regulatory function. Chromatin immunoprecipitation (ChIP) analysis revealed that overexpression of p300 elevated the level of histone H3 acetylation on the hPTTG promoter. Additionally, the NF-Y sites at the hPTTG promoter exhibited a synergistic effect on upregulation of hPTTG through interacting with p300. We also found that treatment of 293T cells with the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) increased hPTTG promoter activity. Meanwhile, we provided evidence that HDAC3 decreased hPTTG promoter activity. These data implicate an important role of the histone acetylation modification in the regulation of hPTTG.
SMAD-4在肿瘤抑制方面有重要作用,但它在肿瘤发生中的作用及其与细胞周期进程中的一种关键调控因子——PTEN(phosphatase and tensin homolog deleted on chromosome 10)的关系仍存在争议.分别在人胚肾细胞(293T)及人胃癌细胞(MGC-803)中研究SMAD-4及TGF-β信号通路对PTEN基因表达的影响.结果发现,在293T细胞中,SMAD-4与TGF-β促进PTEN表达,而MGC-803细胞中,SMAD-4与TGF-β抑制PTEN转录.进一步研究发现,胃癌细胞中,SMAD-4与转化生长因子β(TGF-β)对PTEN的抑制可被PD98059(MEK抑制剂)解除.此外,SMAD-4的核转移也明显促进PTEN表达,并且PD98059存在下,SMAD-4与TGF-β协同刺激可促进胃癌细胞凋亡.综上,实验发现,SMAD-4作为一种co-Smad蛋白,通过TGF-β信号途径影响PTEN表达.
