Department of Cellular and Molecular Biology, Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Genes (Basel). 2024 Apr 25;15(5):543. doi: 10.3390/genes15050543.
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 (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.
细胞衰老（Cellular senescence）是一种不可逆的生长停滞，可作为癌症发生和进展的障碍。组蛋白改变是复制衰老过程中的主要事件之一。然而，关于 H3.3 在细胞衰老中的功能知之甚少。在这里，我们发现 H3.3 的下调诱导了生长抑制，并出现了衰老相关异染色质焦点（Senescence-associated heterochromatin foci，SAHF）和β-半乳糖苷酶（β-galactosidase，SA-β-gal）活性等衰老样表型。此外，H3.3 的耗竭诱导了依赖 p53/p21 途径的衰老样表型。此外，我们鉴定出 miR-22-3p，一种肿瘤抑制 miRNA，作为组蛋白变体 H3.3（Histone variant H3.3）的上游调节剂，该基因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。总之，我们的研究表明 H3.3 在调节细胞衰老中发挥功能作用，是癌症治疗的有前途的靶点。
