School of Forensic Medicine, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
The Affiliated People's Hospital of Xinxiang Medical University, Henan Province, Xinxiang, 453003, People's Republic of China.
Med Oncol. 2022 Jun 6;39(8):111. doi: 10.1007/s12032-022-01720-0.
The ubiquitination process, which involves that binding of an ubiquitin protein to certain substrates, regulates several human biological processes and human cancers. Several studies report that the abnormal expression of quite a few E3 ubiquitin ligases could play critical role in carcinogenic process and cancer progression. In our current study, we identify UHRF1 (Ubiquitin Like with PHD And Ring Finger Domain 1) is an important regulator for breast cancer growth. UHRF1 depletion significantly decreases breast cancer growth in vitro and in vivo. Clinical data analysis reveals that UHRF1 is dramatically elevated in breast cancer, compared to normal breast tissue. UHRF1 correlates with poor survival in luminal type of breast cancer patients, but not in ER-negative groups. The molecular biological studies show that UHRF1 localizes in the nuclear and interact with ERα via its SRA domain, which subsequently inhibits K48-linked ubiquitination of ERα and enhances ERα stability. Our study provides a novel function of UHRF1 in regulation estrogen signaling in breast cancer and a promising target for breast cancer therapeutics.
泛素化过程涉及将泛素蛋白与某些底物结合，调节多种人类生物过程和人类癌症。几项研究报告称，相当数量的 E3 泛素连接酶的异常表达可能在致癌过程和癌症进展中发挥关键作用。在我们目前的研究中，我们确定 UHRF1（具有 PH 和环指域的泛素样物 1）是乳腺癌生长的重要调节剂。UHRF1 耗竭显著降低了体外和体内乳腺癌的生长。临床数据分析显示，与正常乳腺组织相比，UHRF1 在乳腺癌中显著升高。UHRF1 与 luminal 型乳腺癌患者的不良生存相关，但与 ER 阴性组无关。分子生物学研究表明，UHRF1 定位于核内，并通过其 SRA 结构域与 ERα 相互作用，随后抑制 ERα 的 K48 连接泛素化并增强 ERα 的稳定性。我们的研究为 UHRF1 在调节乳腺癌中的雌激素信号转导方面提供了新的功能，并为乳腺癌治疗提供了有前途的靶点。
