Ubiquitin-specific protease 7 promotes the growth and oncogenic potential of acute myeloid leukemia cells through the deubiquitination and upregulation of LRRK2.

Leucine-rich repeat kinase 2 (LRRK2), a large protein with kinase and GTPase activities, regulates various cellular pathways, including autophagy, endocytosis, and mitochondrial dynamics. LRRK2, extensively studied in the context of Parkinson's disease is functionally impaired in other pathological conditions as well, including inflammatory bowel disease, cancer, and cardiovascular diseases. Despite its critical functions, the mechanisms controlling LRRK2 protein stability are not fully understood. Recent studies suggest that the ubiquitin-proteasome system plays a key role in regulating LRRK2 stability. However, the relationship between deubiquitinating enzymes and LRRK2 has not been fully understood. In this study, we identified ubiquitin-specific protease 7 (USP7) as the novel deubiquitinating enzyme that positively regulates LRRK2 by preventing its degradation through ubiquitin-proteasome system. We demonstrated that USP7 directly binds to LRRK2 and promotes its accumulation by deubiquitinating K48-linked polyubiquitin chains. Notably, among various types of cancer, the highest and most significant expression of these two genes was observed in acute myeloid leukemia (AML). We also found that inhibition or knockdown of USP7 suppressed AML cell growth via downregulation of LRRK2, and this effect was partially reversed by LRRK2 overexpression. Furthermore, LRRK2 overexpression significantly increased both the colony formation and cell invasion rates in AML cells, compared to the downregulation of USP7. Taken together, our findings identify USP7 as a novel deubiquitinating enzyme of LRRK2 that positively regulates its stability and plays an oncogenic role in AML, with implications for AML cancer progression and potential therapeutic targets.