Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
GW Cancer Center, The George Washington University, Washington, DC, 20052, USA.
Cell Death Dis. 2021 Apr 1;12(4):341. doi: 10.1038/s41419-021-03635-6.
The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.
JAK2/STAT 通路在许多癌症中被过度激活，这种过度激活与不良的临床预后和耐药性有关。调节 JAK2 活性的机制很复杂。尽管 JAK2 在核和细胞质之间的易位是一个重要的调节机制，但 JAK2 易位如何被调节以及这种易位的生理功能仍然知之甚少。在这里，我们发现蛋白酶 SENP1 直接与 JAK2 相互作用并使其去 SUMO 化，JAK2 的去 SUMO 化导致其在细胞质中积累，在细胞质中 JAK2 被激活。值得注意的是，这种新的 SENP1/JAK2 轴在依赖转录因子 RUNX2 的铂耐药卵巢癌中被激活，而激活的 RUNX2/SENP1/JAK2 对卵巢癌的铂耐药性至关重要。为了探索抗 SENP1/JAK2 治疗铂耐药卵巢癌的应用，我们发现 SENP1 缺失或 SENP1 抑制剂 Momordin Ic 的治疗显著克服了卵巢癌的铂耐药性。因此，这项研究不仅确定了一种调节 JAK2 活性的新机制，而且为通过靶向 SENP1/JAK2 通路治疗铂耐药卵巢癌提供了一种潜在的方法。
