高水平的H2A。Z促进黑色素瘤细胞增殖并与不良预后相关。然而,两种截然不同的H2A的作用。黑色素瘤中的Z组蛋白伴侣复合物SRCAP和P400-TIP60仍不清楚。这里,我们表明SRCAP的单个亚基耗尽,P400和VPS72(YL1)不仅导致H2A的损失。Z沉积到染色质中,但也减少了黑素瘤细胞中H4的乙酰化。H4乙酰化的这种丧失尤其在与H2A直接结合的细胞周期基因的启动子处发现。Z和它的监护人,提示H2A之间的协调调节。Z沉积和H4乙酰化促进它们的表达。三个亚基的击倒下调E2F1及其靶标,导致类似于H2A的细胞周期停滞。Z损耗。然而,不像H2A。Z缺乏,共享H2A的损失。Z伴侣亚基YL1诱导细胞凋亡。此外,YL1在黑素瘤组织中过度表达,其上调与患者预后不良有关。一起,这些发现为未来靶向H2A提供了理论基础.Z伴侣作为黑色素瘤治疗的表观遗传策略。
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.