Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen‐induced cell transformation

Abstract

Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen-induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p-H3S10) and Ser28 (p-H3S28) was upregulated by 1.5-4.8 folds and 2.1-4.3 folds, respectively in aflatoxin B -transformed hepatocytes L02 cells (L02RT-AFB ), benzo(a)pyrene-transformed HBE cells (HBERT-BaP), and coke oven emissions-transformed HBE cells (HBERT-COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage-independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p-H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen-induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p-H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p-H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes.

Non‐SMC condensin I complex subunit H enhances proliferation, migration, and invasion of hepatocellular carcinoma

“…Previous studies have reveals that NCAPH transcript is present in proliferating cells and preceded by phosphorylation of histone H3 at Ser‐10 . Various studies suggested that phosphorylation of histone H3 serine contributed to the HCC progression . Thus, we hypothesis that NCAPH could promotes HCC progression.…”

“…15,16 Various studies suggested that phosphorylation of histone H3 serine contributed to the HCC progression. 17 and CFA assay. To further verify our results, we established NCAPHoverexpressing cell lines.…”

Potential coordination role between O-GlcNAcylation and epigenetics

“…Further study confirmed that H3S10 phosphorylation provides a binding platform for the phospho-binding 14-3-3 proteins and histone acetyltransferase MOF to trigger acetylation of histone H4 at lysine 16 (H4K16ac), and H3S10 phosphorylation and H4K16ac further coordinatively regulate the binding site for bromodomain protein BRD4 (Zippo et al, 2009 ). Moreover, in addition to up-regulation of H3S10 phosphorylation in hepatocellular carcinoma and primary lung cancer (Zhu et al, 2016 ), there is sufficient evidence to prove that H3S10 phosphorylation is responsible for neoplastic cell transformation and oncogene c-fos/c-Jun activation (Choi et al, 2005 ), suggesting the important coordinative role between O -GlcNAcylation and other histone modifications in tumor development.…”

Formaldehyde Exposure and Epigenetic Effects: A Systematic Review

“…Scientific evidence has been emerging concerning the role of histone post-translational modifications in a multitude of DNA related processes, such as DNA damage repair, DNA replication, and transcription of tumor-related genes [51,52]. In particular, the dysregulation of histone H3 phosphorylation, reported following FA exposure, may perturb cellular pathways involved in human cancer development [30,32].…”

“…In fact, it is known that in interphase cells, such phosphorylation phenomena are involved in the chromatin remodeling of the promoter regions of specific loci, i.e., FOS and JUN, implicated in tumorigenic processes, while in mitotic cells, they are responsible for the maintaining of chromosome stability and their accurate segregation [53]. Histone H3 phosphorylation was reported in aflatoxin B1-transformed hepatocytes, benzo(a)pyrene-and coke oven emissions-transformed human bronchial epithelial cells in which such modification performed a mediation role in cellular carcinogenic transformation [51]. The phosphorylation of H3S10 has been reported also to be induced by several environmental factors, such as arsenite [54], nickel [55], and UVB [56,57].…”