Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Cell Rep. 2023 May 30;42(5):112479. doi: 10.1016/j.celrep.2023.112479. Epub 2023 May 12.
CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.
CREB/ATF 转录因子 OASIS/CREB3L1 在长期培养的星形胶质细胞中上调，这些细胞由于 DNA 完整性因反复复制而丢失而进入细胞周期停滞。然而，OASIS 在细胞周期中的作用仍未被探索。我们发现，OASIS 在 DNA 损伤后通过直接诱导 p21 将细胞周期阻滞在 G/M 期。OASIS 引起的细胞周期阻滞在星形胶质细胞和成骨细胞中占主导地位，但在成纤维细胞中不起作用，而成纤维细胞依赖于 p53。在脑损伤模型中，围绕损伤核心的反应性星形胶质细胞表现出持续的生长和抑制细胞周期阻滞，导致胶质增生延长。我们发现，由于其启动子的高甲基化，一些神经胶质瘤患者表现出 OASIS 的低表达。通过表观基因组工程特异性去除移植到裸鼠中的神经胶质瘤中的这种高甲基化，可抑制肿瘤发生。这些发现表明 OASIS 是一种关键的细胞周期抑制剂，具有作为肿瘤抑制因子的潜力。
