High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400–TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion of SRCAP, P400, and VPS72 (YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.

中文翻译：

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H2A.Z 伴侣聚集在黑色素瘤细胞增殖的 E2F 靶基因上


高水平的 H2A.Z 会促进黑色素瘤细胞增殖并与不良预后相关。然而，两种不同的 H2A.Z 组蛋白伴侣复合物 SRCAP 和 P400-TIP60 在黑色素瘤中的作用仍不清楚。在这里，我们发现 SRCAP、P400 和 VPS72 (YL1) 的单个亚基缺失不仅会导致 H2A.Z 沉积到染色质中的损失，还会导致黑色素瘤细胞中 H4 乙酰化的减少。这种 H4 乙酰化的丧失尤其出现在与 H2A.Z 及其伴侣直接结合的细胞周期基因的启动子处，表明 H2A.Z 沉积和 H4 乙酰化之间存在协调调节以促进其表达。三个亚基中每一个的敲低都会下调 E2F1 及其靶标，导致类似于 H2A.Z 耗竭的细胞周期停滞。然而，与 H2A.Z 缺陷不同，共享 H2A.Z 分子伴侣亚基 YL1 的缺失会诱导细胞凋亡。此外，YL1 在黑色素瘤组织中过度表达，其上调与患者预后不良相关。总之，这些发现为未来将 H2A.Z 分子伴侣作为黑色素瘤治疗的表观遗传策略提供了理论依据。