Exploring The Mechanism Of Synergistic Activation Of HIV-1 Gene Transcription By HMBA And Prostratin Cotreatment&the Chemosensitization Effects Of JQ1 In Cancer Cells

In the past decade,much emphasis has been put on the transcriptional activation of HIV-1,which is proposed as a promised strategy for eradicating latent HIV-1 provirus.Two drugs,prostratin and Hexamethylene bisacetamide(HMBA)have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination,although their cellular target(s)are currently not well understood,especially under drug combination.Here,we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms.While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation,HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20,a negative feedback regulator in the NF-κB signaling pathway.In addition,HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα,thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB,a prerequisite for stimulation of transcription initiation.Thus,by blocking the negative feedback circuit,HMBA functions as a signaling enhancer of the NF-κB signaling pathway.Cells require transcription for basic processes,such as survival,cell growth and differentiation.Transformation highly correlates with abnormal transcription of oncogenes or other transcription factors in cancer cells.For many years,genotoxic drugs have been administered to combat cancer.In fact,several compounds that reduce cancer cell proliferation also directly or indirectly affect normal cells,a characteristic that mechanistically contributes to their cytotoxicity,so have a lot limit in the clinical application.Interestingly,several studies in various models have demonstrated that oncogenically transformed cells are more susceptible to chemotherapy drugs in response to transcriptional inhibition.Here,we found that BET inhibitor JQ1 combined with doxrubicin,HU,cisplatin et chemotherapy agents,its cytotoxic activity was dramatically enhanced in colon cancer cell(HCT116).Whereas,the combined effect appears to be more pronounced in the p53 wild type cells than in p53 null cells.Suppression of p53 using shRNA also led to robust apoptosis in HCT116 cell.JQ1 combined with doxrubicin may undergo apoptosis in a p53-dependent and independent manner.The apoptotic effects of JQ1 combined with doxorubicin result in the downregulation of expression of anti-apoptotic factor Bcl-2,enhanced apoptotic factor Bim.altering the balance of apoptotic and anti-apoptotic factors to favor apoptosis,JQ1 and Dox also lead to the inhibition of c-Myc expression and the stimulation of p53.Suppression of Brd4 using shRNA led to remarkable apoptosis in HCT116 cell combined with doxrubicin.Thus,the basal transcription machinery is an increasingly important target for cancer therapies.