The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

中文翻译：

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乳腺癌恶性肿瘤受 MacroH2A2/TM4SF1 轴、AKT/NF-κB 通路和 MMP13 表达升高的调节

组蛋白变体 MacroH2A (mH2A) 通过表观遗传调控影响基因表达。mH2A 同工型的肿瘤抑制功能已在多种癌症类型中被报道，但很少有研究调查 mH2A2 在乳腺癌病理生理学中的功能作用。本研究旨在通过探索mH2A2的下游调控机制来确定mH2A2在乳腺癌发生和进展中的重要性。mH2A2 的敲低促进了乳腺癌细胞的迁移和侵袭，而其过表达则表现出相反的效果。体内实验表明，增加 mH2A2 表达可减少肿瘤生长和肺转移。微阵列分析表明，TM4SF1 成为与 mH2A2 相关的可能靶标，因为它在乳腺癌细胞系中受到显着抑制，在乳腺癌细胞系中，mH2A2 在 mH2A2 敲低后表现出两倍以上上调的基因中过度表达。抑制TM4SF1可减少体内外乳腺癌细胞的迁移、侵袭、肿瘤生长和转移。TM4SF1 耗竭逆转了 mH2A2 敲低引发的攻击性增加，表明 mH2A2 和 TM4SF1 之间存在密切的相互作用。我们的研究结果还强调了 mH2A2/TM4SF1 轴在激活 AKT/NF-κB 通路中的作用。因此，激活的 NF-κB 信号传导导致 MMP13 的表达和分泌增加，MMP13 是一种有效的转移促进剂。总之，我们认为 mH2A2/TM4SF1 轴与 AKT/NF-κB 通路的协调调控以及随后 MMP13 表达的升高构成了控制乳腺癌恶性肿瘤的关键因素。