Loss of Histone H4K20 Trimethylation Occurs in Preneoplasia and Influences Prognosis of Non–Small Cell Lung Cancer

Abstract

Purpose: Epigenetic modifications of histone have crucial roles in the control of gene activity, nuclear architecture, and genomic stability. In this respect, they may contribute to the development and progression of cancer. We investigated whether epigenetic changes of histone H4 are involved in lung carcinogenesis. Experimental Design: Epigenetic modifications of histone H4 were studied by immunohistochemistry in normal lung and 157 lung carcinoma using antibodies specifically recognizing the acetylated (Ac) lysines 5 (K5), K8, K12, K16, and trimethylated (me3) K20 residues of histone H4. Western blotting was used to validate the immunohistochemistry results. H4K20me3 was also studied in 17 preneoplastic lesions. Expression of the Suv4-20h1/2 trimethyltransferases was analyzed by quantitative reverse transcription-PCR in a subset of tumor samples. Results: As compared with normal lung, cancer cells displayed an aberrant pattern of histone H4 modifications with hyperacetylation of H4K5/H4K8, hypoacetylation of H4K12/H4K16, and loss of H4K20 trimethylation. Alteration of H4K20 trimethylation was frequent in squamous cell carcinoma (67%) and was observed in early precursors lesions in which the level of H4K20me3 staining strongly decreased with disease progression. In adenocarcinoma, the down-regulation of H4K20me3 was less frequent (28%) but allowed the identification of a subgroup of stage I adenocarcinoma patients with reduced survival (P = 0.007). Loss of H4K20 trimethylation was associated with decreased expression of Suv4-20h2, a specific H4K20 trimethyltransferase involved in telomere length maintenance. Conclusions: Our findings indicate an important role of histone H4 modifications in bronchial carcinogenesis and highlight H4K20me3 as a candidate biomarker for early detection of and therapeutic approaches to lung cancer.Lung cancer is the leading cause of death from cancer among males in Europe and both men and women in the United States. Non -small cell lung cancer (NSCLC) accounts for almost 80% of such deaths (1 -3). In spite of diagnosis and treatment improvements, the 10-year overall lung cancer survival is less than 10%, claiming more deaths than breast, colon, and prostate cancers all together. Early diagnosis allowing surgical resection with a 60% to 80% 5-year survival is done in only less than 25% of the patients. Therefore, the identification of the molecular biomarkers of clonal selection in lung cancer as well as the comprehension of the mechanisms of their participation in the lung carcinogenesis process are required to establish the prognostic factors of progression of preneoplastic and invasive tumors toward earlier diagnosis, and to define more efficient therapies with lower side effects.Lung cancer is the end result of a process that associates multifocal morphologic transformation and multistep accumulation of molecular abnormalities (4). The clonal selection leading to proliferation and invasion is achieved by disruption of the cell growth controls, with a tumor progression k...

Lung cancer

“…Some clues as to how these cancer specific histone modifications arise are emerging. The demonstration that loss of H4K20me3 correlates with decreased expression of the histone methyltransferase SUV4-20H2, 44 fits well with a recent study showing that Suv4-20 h-double-null mice have lost nearly all H4K20me3 and H4K20me2 states. 45 Similarly, reduced mRNA levels of the MYST Tip60 HAT 46 could explain the hypoacetylation of Histone H4K16, as this enzyme mediates the H4K16 acetylation.…”

“…In this study, cancer cells exhibited a gain of H4K5ac and H4K8ac and a loss of H4K12ac, H4K16ac and H4K20me3. 44 Interestingly, loss of H4K20me3 already occurs in early precursors lesions of squamous cell carcinoma and increases with disease progression. The finding that these changes occurs so soon in the course of lung tumorigenesis indicate that they might be relevant steps in the transformation process.…”

“…44 Changes in global level of individual histone modifications also influence prognosis. Loss of H4K20me3 correlates with reduced survival in patients with stage I adenocarcinoma.…”

“…Loss of H4K20me3 correlates with reduced survival in patients with stage I adenocarcinoma. 44 The epigenetic pattern of H3K4me2, H2AK5ac and H3K9ac influences the clinical outcome of NSCLC patients, especially in early-stage tumors. 54 The cellular levels of H3K4me2 and H3K18ac have also been reported as independent predictors of clinical outcome in lung adenocarcinoma, extensive DNA hypomethylation at repetitive sequences has also been observed in lung tumors.…”

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

“…Alterations in histone lysine methylation are associated with clinical prognosis of lung cancer (13,14). For example, global levels of trimethylated H4K20, a gene-repressive mark, are decreased in squamous cell carcinomas, and its low levels correlate with poor prognosis (14).…”