Cancer cells exhibit alterations in histone modification patterns at individual genes and globally at the level of single nuclei in individual cells. We demonstrated previously that lower global/cellular levels of histone H3 lysine 4 dimethylation (H3K4me2) and H3K18 acetylation (ac) predict a higher risk of prostate cancer recurrence. Here we show that the cellular levels of both H3K4me2 and H3K18ac also predict clinical outcome in both lung and kidney cancer patients, with lower levels predicting significantly poorer survival probabilities in both cancer groups. We also show that lower cellular levels of H3K9me2, a modification associated with both gene activity and repression, is also prognostic of poorer outcome for individuals with either prostate or kidney cancers. The predictive power of these histone modifications was independent of tissue-specific clinicopathological variables, the proliferation marker Ki-67, or a p53 tumor suppressor mutation. Chromatin immunoprecipitation experiments indicated that the lower cellular levels of histone modifications in more aggressive cancer cell lines correlated with lower levels of modifications at DNA repetitive elements but not with gene promoters across the genome. Our results suggest that lower global levels of histone modifications are predictive of a more aggressive cancer phenotype, revealing a surprising commonality in prognostic epigenetic patterns of adenocarcinomas of different tissue origins.

SUMMARY Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason why cells regulate these levels has been unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pHi). As pHi decreases, histones are globally deacetylated by histone deacetylases (HDACs), and the released acetate anions are coexported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pHi. Conversely, global histone acetylation increases as pHi rises, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pHi, particularly compromising pHi maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation throughout the genome. Thus, acetylation of chromatin functions as a rheostat to regulate pHi with important implications for mechanism of action and therapeutic use of HDAC inhibitors.

Adenovirus small early region 1a (e1a) protein drives cells into S phase by binding RB family proteins and the closely related histone acetyl transferases p300 and CBP. The interaction with RB proteins displaces them from DNA-bound E2F transcription factors, reversing their repression of cell cycle genes. However, it has been unclear how the e1a interaction with p300 and CBP promotes passage through the cell cycle. We show that this interaction causes a threefold reduction in total cellular histone H3 lysine 18 acetylation (H3K18ac). CBP and p300 are required for acetylation at this site because their knockdown causes specific hypoacetylation at H3K18. SV40 T antigen also induces H3K18 hypoacetylation. Because global hypoacetylation at this site is observed in prostate carcinomas with poor prognosis, this suggests that processes resulting in global H3K18 hypoacetylation may be linked to oncogenic transformation.The adenovirus small e1a protein drives contact-inhibited primary cells through the cell cycle dependent on three conserved regions (CRs) in e1a ( fig. S1) (1). e1a is not a DNA binding protein, but it binds several other proteins. e1a CR2 binds the retinoblastoma protein (RB) and its paralogs p107 (RBL1) and p130 (RBL2) with high affinity and, together with a lower affinity binding region within CR1, displaces RB proteins from E2F family transcription factors (heterodimers of E2F1 through E2F5 with DP1 or DP2) (1-3). Release of RB family proteins and their associated repressing chromatin modifying activities (4) results in de-repression of cell cycle genes (1). Although the N terminus of e1a is not as extensively conserved among primate adenoviruses as CR1 and CR2, it is nonetheless well conserved among these viruses (5) and is required to drive cells into the cell cycle (1). The N terminus and residues in CR1

Background:Little is known about potential regulation of non-sirtuin HDACs by cellular metabolites. Results: HDAC activity is stimulated by conjugated CoA derivatives and NADPH and is inhibited by free CoA. Conclusion: Cellular metabolites required for anabolism directly stimulate HDAC activity. Significance: Cellular HDAC activity may be modulated in response to the metabolic state of a cell.