Abstract
IntroductionLoss of histone H4 lysine 20 trimethylation (H4K20me3) is associated with multiple cancers, but its role in breast tumors is unclear. In addition, the pathological effects of global reduction in H4K20me3 remain mostly unknown. Therefore, a major goal of this study was to elucidate the global H4K20me3 level in breast cancer tissue and investigate its pathological functions.MethodsLevels of H4K20me3 and an associated histone modification, H3 lysine 9 trimethylation (H3K9me3), were evaluated by immunohistochemistry in a series of breast cancer tissues. Univariate and multivariate clinicopathological and survival analyses were performed. We also examined the effect of overexpression or knockdown of the histone H4K20 methyltransferases, SUV420H1 and SUV420H2, on cancer-cell invasion activity in vitro.ResultsH4K20me3, but not H3K9me3, was clearly reduced in breast cancer tissue. A reduced level of H4K20me3 was correlated with several aspects of clinicopathological status, including luminal subtypes, but not with HER2 expression. Multivariate analysis showed that reduced levels of H4K20me3 independently associated with lower disease-free survival. Moreover, ectopic expression of SUV420H1 and SUV420H2 in breast cancer cells suppressed cell invasiveness, whereas knockdown of SUV420H2 activated normal mammary epithelial-cell invasion in vitro.ConclusionsH4K20me3 was reduced in cancerous regions of breast-tumor tissue, as in other types of tumor. Reduced H4K20me3 level can be used as an independent marker of poor prognosis in breast cancer patients. Most importantly, this study suggests that a reduced level of H4K20me3 increases the invasiveness of breast cancer cells in a HER2-independent manner.
Highlights
Loss of histone H4 lysine 20 trimethylation (H4K20me3) is associated with multiple cancers, but its role in breast tumors is unclear
The sections were blocked with 5% bovine serum albumin (BSA) and incubated with primary monoclonal antibodies against H3K9me3 (CMA318) and H4K20me3 (CMA423); the performance of these antibodies has been validated in Western blotting, immunofluorescence microscopy, and enzyme-linked immunosorbent assay (ELISA)
Our results suggest a negative correlation between invasiveness and the level of H4K20me3 expression, as evidenced by the reduction of H4K20me3 level in invasive breast tumor (Table 1), a positive correlation between loss of H4K20me3 and reduction in disease-free survival, which was associated with metastasis (Figure 2B and Table 2), and lower expression of SUV420H2 in more aggressive MDA-MB-231 and BT-474 breast cancer cells (Figure 3A)
Summary
Loss of histone H4 lysine 20 trimethylation (H4K20me3) is associated with multiple cancers, but its role in breast tumors is unclear. More effective markers for prediction of patients’ outcomes are still needed. Epigenetic alterations such as DNA methylation and histone modifications occur in many cancers (reviewed in [6,7,8,9]). Loss of histone H4 lysine 20 trimethylation (K20me3) is considered a hallmark of human cancer and a potential prognostic marker in many types of cancer other than breast cancer [10,13,14,15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
