TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer

Abstract

Background/Aim: In breast cancer, initiation of carcinogenesis leads to epigenetic dysregulation, which can lead for example to the loss of the heterochromatin skeleton SUV39H1/H3K9me3/HP1 or the supposed secondary skeleton TIP60/P400/H4K12ac/BRD (2/4), which allows the maintenance of chromatin integrity and plasticity. This study investigated the relationship between TIP60, P400 and H4K12ac and their implications in breast tumors. Materials and Methods: Seventy-seven patients diagnosed with breast cancer were included in this study. Chromatin immunoprecipitation (ChIP) assay was used to identify chromatin modifications. Western blot and reverse transcription and quantitative real-time PCR were used to determine protein and gene expression, respectively. Results: We verified the variation in H4K12ac enrichment and the colocalization of H4K12ac and TIP60 on the euchromatin and heterochromatin genes, respectively, by ChIP-qPCR and ChIP-reChIP, which showed an enrichment of H4K12ac on specific genes in tumors compared to the adjacent healthy tissue and a co-localization of H4K12ac with TIP60 in different breast tumor types. Furthermore, RNA and protein expression of TIP60 and P400 was investigated and overexpression of TIP60 and P400 mRNA was associated with tumor aggressiveness. Conclusion: There is a potential interaction between H4K12ac and TIP60 in heterochromatin or euchromatin in breast tumors. Breast cancer is the most frequent cancer (24.2% new cases in 2018) and the leading cause of cancer-related death (15% in 2018) (1). The majority of breast cancers are sporadic (non-hereditary), representing 80 to 90% of breast cancers (2). Deregulation of chromatin integrity and plasticity is among the causes of sporadic cancer (3). They occur at the epigenetic level in the different compartments of chromatin, which are heterochromatin (compacted chromatin) that inhibits gene expression, and euchromatin (relaxed chromatin) that promotes gene transcription. These chromatin states are maintained by so-called epigenetic proteins, which, by placing groups or marks on the histones, allow entry or exit from one state to another (4-6). Among these proteins, SUV39H1, which is a histone methyltransferase (HMT) that adds the H3K9me3 marker on the site where the HP1 protein will bind, thus forming the SUV39H1/H3K9me3/HP1 skeleton which keeps the chromatin closed and inhibits transcription in the heterochromatin region (7, 8). Heterochromatin houses inactive genes such as numerous oncogenes; the loss of this structure would lead to the transcription of oncogenes. Several studies have shown a loss of the SUV39H1 protein in cancer, but also a loss of the SUV39H1/H3K9me3/HP1 skeleton during the onset of carcinogenesis (7, 9). The acetyl-transferases (HAT) such as TIP60 are able to add acetyl groups on the N-terminal tails of histones resulting in the opening of the chromatin leading to euchromatin (10). TIP60 is also capable of acetylating non-histone proteins such as p53 and ATM allowing their activation (11-13). Many studies have s...

SUV39H1 Expression as a Guideline for Omitting Radiotherapy in Lymph Node-positive Triple-negative Breast Cancer Patients

“…SUV39H1 forms the SUV39H1/H3K9me3/HP1 structure, which maintains chromatin compaction and inhibits transcription in the heterochromatin region containing inactive oncogenes. Loss of this structure during breast cancer carcinogenesis leads to oncogene transcription (17). Previous studies have also demonstrated that the inhibition of SPRY4 expression, a factor known to suppress migration and stem cell-related properties in breast carcinoma cells (18), can be achieved through the recruitment of SUV39H1 by lncRNA interaction.…”

HBV confers innate immune evasion through triggering HAT1/acetylation of H4K5/H4K12/miR‐181a‐5p or KPNA2/cGAS‐STING/IFN‐I signaling

“…21 HAT1 catalyzes the acetylation of newly synthesized histone H4 at lysines 5 and 12 (H4K5 and H4K12), 19,20,22 and can be recruited to the promoter or enhancer region of a gene by histone modification enzymes to enhance gene transcription. 23,24 Overexpressed HAT1 regulates tumor immunity by increasing programmed death-ligand 1 expression in pancreatic cancer. 25 Recently, our group reported that HAT1 is able to promote HBV replication by modulating H4K5 and H4K12.…”

“…Our group previously found that HBV could upregulate HAT1 through the HBx‐activated transcription factor Sp1 21 . HAT1 catalyzes the acetylation of newly synthesized histone H4 at lysines 5 and 12 (H4K5 and H4K12), 19,20,22 and can be recruited to the promoter or enhancer region of a gene by histone modification enzymes to enhance gene transcription 23,24 . Overexpressed HAT1 regulates tumor immunity by increasing programmed death‐ligand 1 expression in pancreatic cancer 25 .…”

Investigating mechanisms of ovotoxicity of Perfluorooctanoic acid and Zearalenone exposure and the influence of altered metabolic status on ovarian function

“…Histone H4 acetylation at lysine 12 (H4K12ac) recruits DDR proteins and has been associated with chromatin restoration, increased transcription, and is responsible for interaction with other proteins in the chromatin structure (Hunt et al 2013). Levels of H4K12ac can be dependent on estrogen receptor α (ERα) activity (Nagarajan et al 2015) and decreased H4K12ac protein levels are observed in breast tumors (Idrissou et al 2020), potentially indicating that tissues with ER, including the ovary, can be targeted by alterations in levels of H4K12, leading to adverse effects.…”