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  • br Effect http www apexbt com media diy images wb

    2021-09-18


    Effect of HDACi on Proteasomal Regulation of IκBα and p65 Levels At the transcriptional level, expression of CXCL8, as well as many other proinflammatory chemokines, is regulated by the transcription factor NFκB, which is constitutively activated in solid cancers, including OC, lung, and breast cancer, and conveys a poor outcome 54, 55, 56. Activation of NFκB is mediated by the Etoricoxib receptor of the IKK complex, which comprises two catalytic subunits, IKKα and IKKβ, and a regulatory subunit IKKγ (NEMO). IKK phosphorylates the NFκB inhibitor, IκBα, resulting in IκBα proteasomal degradation and nuclear translocation of NFκB subunits 57, 58. In addition to phosphorylating IκBα, IKKs can phosphorylate histones and p65 NFκB, thus increasing p65 acetylation, promoter recruitment, and transcriptional activity 57, 58. While the proteasomal degradation of IκBα, resulting in the nuclear translocation and accumulation of NFκB subunits, represents a general step in NFκB activation, the specificity and duration of NFκB-regulated responses are mediated by the protein composition of NFκB complexes and their post-translational modifications 59, 60, 61, 62, 63. The NFκB family includes five structurally related proteins, p65 (RelA), p50, p52, c-Rel, and RelB, which form homo- and heterodimers; p65/p50 heterodimers are the most abundant dimers. In addition to IκBα, the p65 subunit of NFκB can also undergo proteasomal degradation [63]. Thus, inhibition of proteasome activity can stabilize both IκBα and p65 NFκB, potentially resulting in two diametrically different outcomes in the regulation of NFκB-transcriptional activity. Since HDACi can modulate the proteasome activity 5, 64, 65, they can also inhibit or activate the NFκB-dependent transcription, depending on the cellular context. Inhibition of HDAC activity with pan-HDACi reduces expression of the catalytic beta subunit of the proteasome, resulting in inhibition of the inducible proteasomal degradation of IκBα [65]. Therefore, in stimulated immune cells, HDAC inhibition is likely to inhibit the inducible cytoplasmic degradation of IκBα, thus preventing the nuclear translocation of NFκB subunits and NFκB-dependent transcription, as observed in stimulated leukocytes 32, 33, 34, 35, 36, 37. The importance of cell stimulation for the HDACi-mediated suppression of NFκB-dependent transcription is evident from the study by Grabiec et al.[35]. In the absence of cell stimulation, exposure of human macrophages to TSA had no influence on basal IL-6 or TNF expression, but TSA inhibited IL-6 and TNF expression in TNF- or LPS-stimulated macrophages [35]. However, in most cancer cells, NFκB is constitutively activated, and the NFκB proteins are already localized in the nucleus. Thus, the HDACi-mediated stabilization of cytoplasmic IκBα is likely to have little effect on the nuclear levels and activity of NFκB in cancer cells. Instead, HDACi may prevent the proteasomal degradation of nuclear p65, thus increasing its nuclear accumulation and promoter binding (Figure 2). Indeed, several studies have demonstrated that HDACi increase the nuclear p65 levels in cancer cells 24, 26, 39, 40, 66. For example, in NSCLC and OC cells, pan-HDACi induce IKK-dependent p65 nuclear accumulation, resulting in increased CXCL8 expression 24, 26. Furthermore, several studies have shown that HDACi increase IKK activity and IKK-dependent promoter and p65 acetylation, resulting in increased p65 transcriptional activity in cancer cells 23, 26, 38, 39, 66, 67.
    HDACi-Induced CXCL8 Expression in Solid Cancer Cells Is p65 and IKK Dependent In contrast to other NFκB-dependent genes, CXCL8 transcription is regulated predominantly by NFκB p65 homodimers 68, 69. Seven acetylated lysines have been identified within p65 NFκB: K122, 123, 218, 221, 310, 314, and 315 [62]. Acetylation of K122 and 123 reduces p65 binding to DNA, and promotes its nuclear export [70]. Acetylation of K221 enhances p65 DNA binding and impairs its binding to IκBα, while acetylation of K310 is required for full transcriptional activity of p65 [60]. Interestingly, acetylation of p65 at K314 and 315 does not affect p65 DNA binding, but facilitates its promoter specificity in stimulated cells 71, 72. Acetylation of p65 is regulated by the HATs, p300 and CBP, and HDAC1, 2, and 3 38, 73, 74, 75, 76, 77, 78, 79. However, the specific regulation of p65 by the individual HATs and HDACs differs in different cells and tissues, and may depend on the cellular status of other transcription factors and coregulators. For example, while p65 was reported to directly interact with HDAC2 in kidney mesangial cells [80], such an interaction was not observed in other cell types 38, 70, 78. Since different acetylation sites differentially regulate the functions and promoter specificity of p65, modulation of p65 acetylation by targeting specific HATs and HDACs might prove useful in targeting specific NFκB-dependent genes.