College of Medicine Depart of Physiology & Cell Biology, University of South Alabama, Mobile, AL 36688, USA.
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36607, USA.
Int J Mol Sci. 2022 Apr 13;23(8):4314. doi: 10.3390/ijms23084314.
Dysregulation of DNA repair is a hallmark of cancer, though few cancer-specific mechanisms that drive the overexpression of DNA repair proteins are known. We previously identified STAT3 as a novel transcriptional regulator of X-ray cross-complementing group 1 (XRCC1), an essential scaffold protein in base excision repair in triple-negative breast cancers. We also identified an inducible response to IL-6 and epidermal growth factor stimulation in the non-tumorigenic embryonic kidney cell line HEK293T. As IL-6 and EGF signaling are growth and inflammatory-inducible responses, we examined if glucose challenge can increase STAT3 activation, promoting adaptive changes in XRCC1 expression in different cell types. Acute high glucose exposure promoted XRCC1 expression through STAT3 activation, increasing the repair of methyl methanesulfonate-induced DNA damage in HEK293T cells and the osteosarcoma cell line U2OS. Sustained exposure to high glucose promoted the overexpression of XRCC1, which can be reversed upon glucose restriction and down-regulation of STAT3 activation. Thus, we have identified a novel link between XRCC1 expression and STAT3 activation following exogenous exposures, which could play a critical role in dictating a cancer cell's response to DNA-damaging agents.
DNA 修复失调是癌症的一个标志，尽管很少有已知的专门驱动 DNA 修复蛋白过表达的癌症特异性机制。我们之前发现 STAT3 是三阴性乳腺癌中碱基切除修复中必不可少的支架蛋白 X 射线交叉互补组 1（XRCC1）的新型转录调节剂。我们还在非致瘤性胚胎肾细胞系 HEK293T 中鉴定出对 IL-6 和表皮生长因子刺激的诱导反应。由于 IL-6 和 EGF 信号是生长和炎症诱导的反应，我们检查了葡萄糖挑战是否可以增加 STAT3 的激活，从而促进不同细胞类型中 XRCC1 表达的适应性变化。急性高葡萄糖暴露通过 STAT3 激活促进 XRCC1 的表达，增加了 HEK293T 细胞和骨肉瘤细胞系 U2OS 中甲基甲磺酸酯诱导的 DNA 损伤的修复。持续暴露于高葡萄糖可促进 XRCC1 的过表达，这种过表达可在葡萄糖限制和 STAT3 激活下调后逆转。因此，我们在细胞外暴露后发现了 XRCC1 表达与 STAT3 激活之间的新联系，这可能在决定癌细胞对 DNA 损伤剂的反应中起着关键作用。
