Department of Molecular Biosciences, The University of Texas at Austin, 2506 Speedway, Austin, TX, 78712, USA.
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, 78712, USA.
Sci Rep. 2022 Mar 8;12(1):3758. doi: 10.1038/s41598-022-07675-6.
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.
基因组稳定性对于生物体发育、细胞内稳态和生存至关重要。DNA 双链断裂尤其具有危害性，会导致细胞转化和致癌激活的环境。组蛋白变体 H2AX 是核小体的必需组成部分，负责启动 DNA 修复过程的早期步骤。H2AX 通过启动信号级联反应来维持基因组稳定性，该级联反应共同作用以促进 DNA 双链断裂修复。最近的研究进展将基因组稳定性与能量代谢联系起来，并且发现代谢的改变会干扰基因组的维持。我们利用全基因组转录谱分析来鉴定参与能量代谢的差异表达基因，比较了对照和 H2AX 缺陷型转移性乳腺癌细胞系，发现 H2AX 缺失导致调节糖酵解的关键基因受到抑制，对己糖激酶-2（HK2）的影响尤为显著。这些观察结果得到了证据的支持，即 H2AX 缺失会削弱糖酵解作用，而通过异位表达 HK2 可以逆转这种作用。利用实验性转移模型，我们发现 H2AX 沉默会阻止转移性乳腺癌细胞 MDA-MB-231 的进展。最有趣的是，在 H2AX 缺陷型细胞中异位表达 HK2 可以恢复其转移潜能。通过使用多个公开可用的数据集，我们发现浸润性乳腺癌患者中 H2AX 的表达水平与糖酵解基因，特别是 HK2 的水平之间存在显著的正相关。这些观察结果与高 H2AX 表达与远处无转移生存时间缩短相关的证据一致。我们的研究结果揭示了组蛋白 H2AX 通过维持 HK2 驱动的糖酵解来控制乳腺癌细胞转移能力的作用。
