Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis

Abstract

Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-jB (NF-jB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-jB activity. Further investigation showed that Zac1 inhibits NF-jB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-jB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.

Hydrogen sulfide ameliorates chronic renal failure in rats by inhibiting apoptosis and inflammation through ROS/MAPK and NF-κB signaling pathways

“…The most abundant form of NF-κB is the heterodimer composed of p50 and p65 38, 39 . In the present study, the protein expressions of p50, p65, and p-p65 in the kidney of rats were measured to investigate the underlying mechanism of H 2 S on the cytokine regulation.…”

Expression and Prognostic Significance of EP300, TP53 and BAX in Clear Cell Renal Cell Carcinoma

“…Interestingly, promoters that are predicted to recruit EP300 protein contain CpG islands and their expression is significantly regulated by methylation and histone acetylation processes (39), and the P1 promoter of the PLAGL1 gene fits this characteristic well (19,40). Since the transcription of PLAGL1 depends on H3 and H4 acetylation in the promoter region (40), the possibility of direct interaction of EP300 and PLAGL1 in ccRCC may justify further research aimed to determine the significance of the observed associations between these factors in the pathogenesis of ccRCC. In conclusion, the results of our study indicate that the expression levels of EP300, TP53 and BAX proteins do not correlate with patient survival in ccRCC and cannot be used to discriminate between low-risk and high-risk patients.…”

Importance of the matriline for genomic imprinting, brain development and behaviour

“…Some of these imprinted genes that are co-expressed in the hypothalamus and placenta correspond to hub-like nodes, being interconnected to the largest number of network genes (Peg3, Ndn,Gnas). Zac1 is known to control neural cellcycle arrest and apoptosis through different pathways and is expressed in the hypothalamus and pituitary [50]. A general feature of such gene networks is to provide robustness against perturbations during development.…”