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  • However HDACi can also increase the acetylation

    2022-01-18

    However, HDACi can also increase the acetylation of other transcription factors that regulate p65 transcriptional activity. The HDACi-induced activation of p65 can be negated by acetylated mk-801 STAT1, which can specifically bind to p65 and inhibit its transcriptional activity 81, 82, 83. Interestingly, acetylated STAT1 was found in chemotherapy-sensitive but not resistant OC mk-801 [84]. Since activated NFκB mediates chemoresistance by inducing the expression of prosurvival genes [58], these data suggest that HDACi-induced STAT1 acetylation suppresses the p65-mediated expression of prosurvival genes, thus modulating chemoresistance. In addition, HDACi can modulate p53 activity and its interaction with p65, thus representing yet another mechanism regulating p65-dependent transcription 6, 85. CXCL8 expression is specifically regulated by class I HDACs, particularly HDAC1, 2, and 3 27, 77, 86, 87. However, since acetylation of different lysines can both activate and inhibit p65 transcriptional activity, HDACs can both induce and repress CXCL8 expression. Indeed, suppression of HDAC1, 2, and 3 was reported to both inhibit and induce CXCL8 expression, depending on the cell type, stimulus, and presence of additional transcriptional regulators 27, 77, 86, 87. In breast cancer cells, knockdown of HDAC1 specifically suppressed CXCL8 expression, resulting in their reduced proliferation and migration [86]. By contrast, in lung cancer cells infected with respiratory syncytial virus, CXCL8 transcription was inhibited by Bcl3-mediated recruitment of HDAC1, indicating that HDAC1 attenuates CXL8 promoter activity under these conditions [87]. Interestingly, while individual suppression of HDAC1, 2, or 3 inhibited CXCL8 expression in OC cells, their simultaneous suppression induced CXCL8 expression, suggesting that HDAC1, 2, and 3 form complexes with other transcriptional regulators and that suppression of HDAC protein levels in these complexes disrupts their function and reduces CXCL8 transcription [27]. In this context, previous studies have shown that, in addition to p65, HDAC1, 2, and 3 form complexes with IκBα, NuRD, N-CoR/SMRT, and other transcriptional activators and repressors important for cancer cell survival and growth 38, 70, 73, 74. Thus, the impact of the pharmacological inhibition of HDACs will likely differ from the effect of HDAC protein suppression. Intriguingly, in OC cells, class I HDACi dramatically increase only the expression of CXCL8, and do not have any substantial effect on the expression of other NFκB-dependent genes, including those encoding TNFα, IL-6, CXCL5, TGFβ1, cIAP-1, Bcl-2, p65, p50, IκBα, CXCR-1, and CXCR2 26, 27. HDACi-induced CXCL8 expression in OC cells is mediated by a gene-specific, IKKβ-dependent recruitment of p65 homodimers to the CXCL8 promoter. In addition, HDAC inhibition increases K314/315 acetylation of p65, and its promoter-specific occupancy at the CXCL8 promoter [26]. HDACi-induced CXCL8 expression is also mediated by IKKβ and p65 NFκB in breast cancer cells [42]. Why do HDACi induce predominantly CXCL8 expression in solid cancer cells? Since HDACi increase the nuclear levels of p65 in cancer cells 24, 26, 39, 40, 66, they may specifically increase the expression of genes regulated by p65 homodimers. In addition, the HDACi-increased K314/315 acetylation of p65 may favor its specific recruitment to the CXCL8 promoter, as observed in OC cells [26]. Thus, HDACi-induced CXCL8 expression in solid tumor cells is likely a result of several HDACi-mediated mechanisms that include the HDACi-increased nuclear accumulation of p65, increased IKK activity and IKK-dependent p65 K314/315 acetylation, and promoter-specific recruitment of K314/315 acetylated p65 homodimers to the CXCL8 promoter (Figure 2).
    Opportunities for Combination Therapies Targeting HDAC and IKK in Solid Tumors Inhibition of IKK activity decreases CXCL8 expression induced by HDAC inhibition in OC cells [26]. Since CXCL8 induces proliferation and survival in cancer cells 26, 44, 45, 46, 47, 48, these data indicate that therapies targeting IKK-mediated CXCL8 expression may increase the effectiveness of HDACi in OC treatment. This is supported by in vitro data demonstrating that suppression of HDACi-induced CXCL8 by small interfering (si)RNAs, or its neutralization by anti-CXCL8 monoclonal antibodies, increases HDACi proapoptotic and antiproliferative effects in OC cells [26], and by in vivo studies demonstrating that suppression of CXCL8 reduces ovarian tumor growth 47, 48. In addition, Sonnemann et al. showed that HDACi and aspirin synergistically induce cell death in OC cells, independently of cyclooxygenase [88]. Since aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), in addition to inhibiting cyclooxygenase activity, inhibit IKK activity [89], it appears plausible that the observed synergistic effect in OC cells was mediated by IKK inhibition and suppression of HDACi-induced CXCL8 expression. Disruption of NFκB-signaling also potentiates the proapoptotic effect of HDACi in other solid cancer cells, including NSCLC, head and neck squamous cell carcinomas, prostate cancer cells, hepatocellular carcinoma, and thyroid cancer 23, 24, 40, 90, 91, 92, 93, 94.