State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, China.
Aging (Albany NY). 2023 Sep 7;15(17):8812-8832. doi: 10.18632/aging.205001.
Deleted in breast cancer 1 (DBC1) was initially identified from a homozygously deleted region in human chromosome 8p21. It has been well established that DBC1 plays a dual role during cancer development. Depending on the physiological context, it can promote or inhibit tumorigenesis. Whether it plays a role in lens pathogenesis remains elusive. In the present study, we demonstrated that DBC1 is highly expressed in lens epithelial cells from different vertebrates and in retina pigment epithelial cells as well. Moreover, DBC1 is SUMOylated through SUMO1 conjugation at K591 residue in human and mouse lens epithelial cells. The SUMOylated DBC1 is localized in the nucleus and plays an essential role in promoting stress-induced apoptosis. Silence of DBC1 attenuates oxidative stress-induced apoptosis. In contrast, overexpression of DBC1 enhances oxidative stress-induced apoptosis, and this process depends on p53. Mechanistically, DBC1 interacts with p53 to regulate its phosphorylation status at multiple sites and the SUMOylation of DBC1 enhances its interaction with p53. Together, our results identify that DBC1 is an important regulator mediating stress-induced apoptosis in lens, and thus participates in control of lens cataractogenesis.
缺失于乳腺癌 1 号（DBC1）最初是从人类染色体 8p21 的纯合缺失区域中鉴定出来的。已经证实 DBC1 在癌症发展过程中具有双重作用。根据生理环境的不同，它可以促进或抑制肿瘤发生。它是否在晶状体发病机制中发挥作用仍不清楚。在本研究中，我们证明了 DBC1 在不同脊椎动物的晶状体上皮细胞和视网膜色素上皮细胞中高度表达。此外，DBC1 通过 SUMO1 在人类和小鼠晶状体上皮细胞中 K591 残基的连接而发生 SUMO 化。SUMO 化的 DBC1 定位于细胞核中，在促进应激诱导的细胞凋亡中起重要作用。DBC1 的沉默可减弱氧化应激诱导的细胞凋亡。相反，DBC1 的过表达增强了氧化应激诱导的细胞凋亡，而这一过程依赖于 p53。在机制上，DBC1 与 p53 相互作用，调节其在多个位点的磷酸化状态，DBC1 的 SUMO 化增强了其与 p53 的相互作用。总之，我们的研究结果表明 DBC1 是一种重要的调节因子，介导晶状体应激诱导的细胞凋亡，从而参与晶状体白内障的发生。
