A Transcriptional Program Mediating Entry into Cellular Quiescence

The balance of quiescence and cell division is critical for tissue homeostasis and organismal health. Serum stimulation of fibroblasts is well studied as a classic model of entry into the cell division cycle, but the induction of cellular quiescence, such as by serum deprivation (SD), is much less understood. Here we show that SS and SD activate distinct early transcriptional responses genome-wide that converge on a late symmetric transcriptional program. Several serum deprivation early response genes (SDERGs), including the putative tumor suppressor genes SALL2 and MXI1, are required for cessation of DNA synthesis in response to SD and induction of additional SD genes. SDERGs are coordinately repressed in many types of human cancers compared to their normal counterparts, and repression of SDERGs predicts increased risk of cancer progression and death in human breast cancers. These results identify a gene expression program uniquely responsive to loss of growth factor signaling; members of SDERGs may constitute novel growth inhibitors that prevent cancer.

细胞静息态与细胞分裂的动态平衡，对于组织稳态（tissue homeostasis）与机体健康至关重要。成纤维细胞的血清刺激作为细胞进入细胞分裂周期的经典模型已被广泛研究，但诸如血清剥夺（serum deprivation, SD）这类诱导细胞静息态的手段，其相关机制目前仍有待深入阐明。本研究显示，血清刺激（serum stimulation, SS）与血清剥夺可在全基因组范围内激活截然不同的早期转录应答，二者最终汇聚至一套晚期对称转录程序。多种血清剥夺早期应答基因（serum deprivation early response genes, SDERGs）——包括推定的肿瘤抑制基因SALL2与MXI1——是血清剥夺诱导下DNA合成终止以及其他血清剥夺相关基因诱导表达所必需的。与对应正常组织相比，SDERGs在多种人类癌症中均呈现协同抑制状态；且SDERGs的抑制水平可预测人类乳腺癌患者的癌症进展与死亡风险升高。上述研究结果鉴定出一套仅对生长因子信号缺失产生特异性应答的基因表达程序；SDERGs家族成员或可作为新型生长抑制因子，发挥预防癌症的作用。