Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, China.
The State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, China.
Life Sci. 2019 Jul 15;229:225-232. doi: 10.1016/j.lfs.2019.05.023. Epub 2019 May 11.
Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells.
Knockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-β-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS).
Our results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.
细胞衰老（cellular senescence）是一种众所周知的癌症预防机制，诱导癌细胞衰老可以增强癌症免疫疗法。然而，细胞衰老的调控机制尚不完全清楚。在细胞衰老过程中发现了动态染色质变化，但其因果关系仍难以捉摸。编码 ATP 依赖性染色质重塑复合物辅助亚基的基因 BAZ1A 在多种细胞衰老模型中表达降低。我们旨在研究 BAZ1A 在调节癌症和正常细胞衰老中的功能作用。
通过慢病毒介导的短发夹 RNA（shRNA）在各种癌细胞系（A549 和 U2OS）和正常细胞（HUVEC、NIH3T3 和 MEF）中敲低 BAZ1A。通过 CCK-8 测定、SA-β-Gal 染色和 EdU 掺入测定等方法定量检测一系列衰老相关表型。
BAZ1A 的敲低（KD）在癌细胞和正常细胞中均诱导了一系列衰老相关表型。BAZ1A-KD 导致 SMAD3 的表达上调，进而激活 p21 编码基因 CDKN1A 的转录，导致人癌细胞（A549 和 U2OS）出现衰老相关表型。
我们的结果揭示了染色质重塑调节剂 BAZ1A 作为正常和癌细胞衰老的新型调节剂，为潜在的癌症治疗提供了新的靶点。
