Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2
Abstract Genomic stability is essential for organismal development, cellular homeostasis, and survival. The DNA double-strand breaks are particularly deleterious, creating an environment prone to cellular transformation and oncogenic activation. The histone variant H2AX is an essential component of...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-07675-6 |
| _version_ | 1819236738581659648 |
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| author | Yue Liu Haojian Li Crystal N. Wilson Hui Jen Bai Myriem Boufraqech Urbain Weyemi |
| author_facet | Yue Liu Haojian Li Crystal N. Wilson Hui Jen Bai Myriem Boufraqech Urbain Weyemi |
| author_sort | Yue Liu |
| collection | DOAJ |
| description | Abstract Genomic stability is essential for organismal development, cellular homeostasis, and survival. The DNA double-strand breaks are particularly deleterious, creating an environment prone to cellular transformation and oncogenic activation. The histone variant H2AX is an essential component of the nucleosome responsible for initiating the early steps of the DNA repair process. H2AX maintains genomic stability by initiating a signaling cascade that collectively functions to promote DNA double-strand breaks repair. Recent advances have linked genomic stability to energetic metabolism, and alterations in metabolism were found to interfere with genome maintenance. Utilizing genome-wide transcripts profiling to identify differentially-expressed genes involved in energetic metabolism, we compared control and H2AX-deficient metastatic breast cancer cell lines, and found that H2AX loss leads to the repression of key genes regulating glycolysis, with a prominent effect on hexokinase-2 (HK2). These observations are substantiated by evidence that H2AX loss compromises glycolysis, effect which was reversed by ectopic expression of HK2. Utilizing models of experimental metastasis, we found that H2AX silencing halts progression of metastatic breast cancer cells MDA-MB-231. Most interestingly, ectopic expression of HK2 in H2AX-deficient cells restores their metastatic potential. Using multiple publicly available datasets, we found a significantly strong positive correlation between H2AX expression levels in patients with invasive breast cancer, and levels of glycolysis genes, particularly HK2. These observations are consistent with the evidence that high H2AX expression is associated with shorter distant metastasis-free survival. Our findings reveal a role for histone H2AX in controlling the metastatic ability of breast cancer cells via maintenance of HK2-driven glycolysis. |
| first_indexed | 2024-12-23T13:09:13Z |
| format | Article |
| id | doaj.art-c92d1554e7c4449992134f98e997cf37 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T13:09:13Z |
| publishDate | 2022-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c92d1554e7c4449992134f98e997cf372022-12-21T17:45:48ZengNature PortfolioScientific Reports2045-23222022-03-0112111210.1038/s41598-022-07675-6Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2Yue Liu0Haojian Li1Crystal N. Wilson2Hui Jen Bai3Myriem Boufraqech4Urbain Weyemi5Department of Molecular Biosciences, The University of Texas at AustinDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Molecular Biosciences, The University of Texas at AustinAbstract Genomic stability is essential for organismal development, cellular homeostasis, and survival. The DNA double-strand breaks are particularly deleterious, creating an environment prone to cellular transformation and oncogenic activation. The histone variant H2AX is an essential component of the nucleosome responsible for initiating the early steps of the DNA repair process. H2AX maintains genomic stability by initiating a signaling cascade that collectively functions to promote DNA double-strand breaks repair. Recent advances have linked genomic stability to energetic metabolism, and alterations in metabolism were found to interfere with genome maintenance. Utilizing genome-wide transcripts profiling to identify differentially-expressed genes involved in energetic metabolism, we compared control and H2AX-deficient metastatic breast cancer cell lines, and found that H2AX loss leads to the repression of key genes regulating glycolysis, with a prominent effect on hexokinase-2 (HK2). These observations are substantiated by evidence that H2AX loss compromises glycolysis, effect which was reversed by ectopic expression of HK2. Utilizing models of experimental metastasis, we found that H2AX silencing halts progression of metastatic breast cancer cells MDA-MB-231. Most interestingly, ectopic expression of HK2 in H2AX-deficient cells restores their metastatic potential. Using multiple publicly available datasets, we found a significantly strong positive correlation between H2AX expression levels in patients with invasive breast cancer, and levels of glycolysis genes, particularly HK2. These observations are consistent with the evidence that high H2AX expression is associated with shorter distant metastasis-free survival. Our findings reveal a role for histone H2AX in controlling the metastatic ability of breast cancer cells via maintenance of HK2-driven glycolysis.https://doi.org/10.1038/s41598-022-07675-6 |
| spellingShingle | Yue Liu Haojian Li Crystal N. Wilson Hui Jen Bai Myriem Boufraqech Urbain Weyemi Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 Scientific Reports |
| title | Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 |
| title_full | Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 |
| title_fullStr | Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 |
| title_full_unstemmed | Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 |
| title_short | Histone H2AX promotes metastatic progression by preserving glycolysis via hexokinase-2 |
| title_sort | histone h2ax promotes metastatic progression by preserving glycolysis via hexokinase 2 |
| url | https://doi.org/10.1038/s41598-022-07675-6 |
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