PDF(Pubmed)
Abstract：
Cellular senescence is an irreversible growth arrest that acts as a barrier to cancer initiation and progression. Histone alteration is one of the major events during replicative senescence. However, little is known about the function of H3.3 in cellular senescence. Here we found that the downregulation of H3.3 induced growth suppression with senescence-like phenotypes such as senescence-associated heterochromatin foci (SAHF) and β-galactosidase (SA-β-gal) activity. Furthermore, H3.3 depletion induced senescence-like phenotypes with the p53/p21-depedent pathway. In addition, we identified miR-22-3p, tumor suppressive miRNA, as an upstream regulator of the H3F3B (H3 histone, family 3B) gene which is the histone variant H3.3 and replaces conventional H3 in active genes. Therefore, our results reveal for the first time the molecular mechanisms for cellular senescence which are regulated by H3.3 abundance. Taken together, our studies suggest that H3.3 exerts functional roles in regulating cellular senescence and is a promising target for cancer therapy.
摘要：
细胞衰老是一种不可逆的生长停滞，是癌症发生和发展的障碍。组蛋白改变是复制衰老过程中的主要事件之一。然而,对H3.3在细胞衰老中的功能知之甚少。在这里，我们发现H3.3的下调诱导了衰老样表型的生长抑制，如衰老相关的异染色质灶（SAHF）和β-半乳糖苷酶（SA-β-gal）活性。此外，H3.3耗竭诱导了p53/p21抑制途径的衰老样表型。此外,我们鉴定了miR-22-3p，肿瘤抑制性miRNA，作为H3F3B(H3组蛋白，家族3B）基因，该基因是组蛋白变体H3.3，取代了活性基因中的常规H3。因此,我们的结果首次揭示了由H3.3丰度调节的细胞衰老的分子机制。一起来看,我们的研究表明,H3.3在调节细胞衰老中发挥功能作用,是一个有前景的癌症治疗靶点.
