Abstract
Epigenetic signaling networks dynamically regulate gene expression to maintain cellular homeostasis. Previously, we uncovered that WEE1 phosphorylates histone H2B at tyrosine 37 (pY37-H2B) to negatively regulate global histone transcriptional output. Although pY37-H2B is readily detected in cancer cells, its functional role in pathogenesis is not known. Herein, we show that WEE1 deposits the pY37-H2B marks within the tumor suppressor gene, isocitrate dehydrogenase 2 (IDH2), to repress transcription in multiple cancer cells, including glioblastoma multiforme (GBMs), melanoma and prostate cancer. Consistently, GBMs and primary melanoma tumors that display elevated WEE1 mRNA expression exhibit significant down regulation of the IDH2 gene transcription. IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), an essential cofactor for the TET family of 5-methylcytosine (5mC) hydroxylases that convert 5-mC to 5-hydroxymethylcytosine (5-hmC). Significantly, the WEE1 inhibitor AZD1775 not only abrogated the suppressive H2B Y37-phosphorylation and upregulated IDH2 mRNA levels but also effectively reversed the ‘loss of 5-hmC’ phenotype in melanomas, GBMs and prostate cancer cells, as well as melanoma xenograft tumors. These data indicate that the epigenetic repression of IDH2 by WEE1/pY37-H2B circuit may be a hitherto unknown mechanism of global 5-hmC loss observed in human malignancies.
Highlights
The precise execution of epigenetic signaling events, which includes both addition and removal of epigenetic marks in a temporally regulated manner, is vital to preserve the chromatin landscape and maintain cellular homeostasis
To better understand how cancer cells may benefit from this newly discovered WEE1 epigenetic activity, we mined our pY37H2B chromatin immunoprecipitation (ChIP)-sequencing data for genes associated with oncogenesis; it revealed that pY37-H2B marks were deposited at an important tumor suppressor gene-the isocitrate dehydrogenase 2 (IDH2)
An increased accumulation of cells in S phase was observed as a result of treatment with AZD1775 (Supplementary Figure 1). These data demonstrate that WEE1 mediated H2B Y37-phosphorylation is a recurrent pro-proliferative epigenetic modification in multiple proliferating cancer cells that can be targeted with the WEE1 inhibitor, AZD1775
Summary
The precise execution of epigenetic signaling events, which includes both addition and removal of epigenetic marks in a temporally regulated manner, is vital to preserve the chromatin landscape and maintain cellular homeostasis. It has become evident that behind every histone or DNA modification, commonly referred to as epigenetic changes, there are a number of regulators that work in a highly orchestrated manner to govern the transcriptional landscape and determine cell fate. Of the 6 known histone tyrosine phosphorylation events, WEE1 directly phosphorylates the histone H2B at tyrosine 37 (pY37-H2B) to negatively regulate global histone transcriptional output in a temporally regulated manner during each cell cycle [7, 13]. To better understand how cancer cells may benefit from this newly discovered WEE1 epigenetic activity, we mined our pY37H2B chromatin immunoprecipitation (ChIP)-sequencing data for genes associated with oncogenesis; it revealed that pY37-H2B marks were deposited at an important tumor suppressor gene-the isocitrate dehydrogenase 2 (IDH2)
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