Uno Yoko, Hayakawa Koji
Laboratory of Genetics, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, 7948555, Japan.
Sci Rep. 2025 Mar 24;15(1):10170. doi: 10.1038/s41598-025-95394-z.
Triple-negative breast cancer (TNBC) is characterized by resistance to conventional treatment and a poor prognosis. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins has been reported to affect cancer progression. However, the key O-GlcNAc proteins involved in TNBC phenotypes remain unclear. Our previous study demonstrated that serine 40 of histone H2A was modified by O-GlcNAcylation (H2AS40Gc). Since S40 is located inside the globular domain of H2A, H2AS40Gc may be involved in the regulation of gene expression by altering chromatin conformation and could serve as the molecular basis for TNBC. The present study showed that H2AS40Gc levels were significantly higher in TNBC than in the other breast cancer subtypes. Using TNBC cells in which H2AS40Gc levels were depleted, we found that H2AS40Gc is required to promote cell proliferation and migration. The underlying mechanism of this promotion involves the accumulation of H2AS40Gc in the promoter region of KDM5B, a demethylase for lysine 4 of histone H3 (H3K4) that represses the expression of KDM5B, resulting in increased H3K4 trimethylation and elevated expression of genes related to proliferation and migration. Our findings clearly indicate that H2AS40Gc functions to promote proliferation and migration through KDM5B suppression and provide new insights into potential therapeutic approaches for TNBC.
三阴性乳腺癌（TNBC）的特点是对传统治疗有抗性且预后较差。据报道，蛋白质的O-连接β-N-乙酰葡糖胺（O-GlcNAc）修饰会影响癌症进展。然而，参与TNBC表型的关键O-GlcNAc蛋白仍不清楚。我们之前的研究表明，组蛋白H2A的丝氨酸40被O-连接N-乙酰葡糖胺化修饰（H2AS40Gc）。由于S40位于H2A的球状结构域内，H2AS40Gc可能通过改变染色质构象参与基因表达调控，并可能作为TNBC的分子基础。本研究表明，TNBC中H2AS40Gc水平显著高于其他乳腺癌亚型。使用H2AS40Gc水平降低的TNBC细胞，我们发现H2AS40Gc是促进细胞增殖和迁移所必需的。这种促进作用的潜在机制涉及H2AS40Gc在KDM5B启动子区域的积累，KDM5B是一种组蛋白H3赖氨酸4（H3K4）的去甲基化酶，可抑制KDM5B的表达，导致H3K4三甲基化增加以及与增殖和迁移相关基因的表达升高。我们的研究结果清楚地表明，H2AS40Gc通过抑制KDM5B发挥促进增殖和迁移的作用，并为TNBC的潜在治疗方法提供了新的见解。
