Abstract
CDKN1C (encoding tumor suppressor p57KIP2) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modifications. In particular, we show that CDKN1C is targeted by histone methyltransferase EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3), and can be strongly activated by inhibition of EZH2 in synergy with histone deacetylase inhibitor. Consistent with the overexpression of EZH2 in a variety of human cancers including breast cancer, CDKN1C in these cancers is downregulated, and breast tumors expressing low levels of CDKN1C are associated with a poor prognosis. We further show that assessing both EZH2 and CDKN1C expression levels as a measurement of EZH2 pathway activity provides a more predictive power of disease outcome than that achieved with EZH2 or CDKN1C alone. Taken together, our study reveals a novel epigenetic mechanism governing CDKN1C repression in breast cancer. Importantly, as a newly identified EZH2 target with prognostic value, it has implications in patient stratification for cancer therapeutic targeting EZH2-mediated gene repression.
Highlights
Cyclin-dependent kinase inhibitors (CDKIs) are a large family of proteins that regulate cell cycle progression, cell proliferation and differentiation
We have previously reported that S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanosin A (DZNep) is able to inhibit histone methylation and depletes the EZH2 complex and the associated H2K27 methylation [23] and combination of DZNep with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) resulted in robust activation of H3K27me3 target genes [16]
We found that CDKN1C can be strongly induced by a combination of DZNep and TSA treatment compared to a modest induction by Aza
Summary
Cyclin-dependent kinase inhibitors (CDKIs) are a large family of proteins that regulate cell cycle progression, cell proliferation and differentiation. CDKIs show widespread involvement in tumor suppression and are deregulated in many types of human cancers by genetic and epigenetic alterations. Loss of expression of CDKIs, such as p16INK4A, due to promoter DNA hypermethylation, is frequent in human cancer and the CDKIs downregulation is associated with aberrant cell proliferation and tumor growth. In addition to promoter DNA methylation, histone modifications play a role in inactivation of the CDK inhibitors. It has been shown that H3K9 methylation can occur at p16INK4A independently of DNA methylation [1]. Inactivation of the INK4A locus by other mechanisms such as Polycomb-associated histone H3K27 methylation have been reported [2,3,4]
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