Targeting Ubiquitin Specific Peptidase 9x With Neogambogic Acid In Osteosarcoma

Osteosarcoma is the most common primary non-hematologic malignancy in children and adolescents.Its high incidence and fast progression leads to high malignancy and metastasis,which results in low long-term survival rate.Surgical amputation is the major treatments for early osteosarcoma.However,the shortness of this treatment is obvious including big surgical trauma,high morbidity and low long-term survival rate.The reason might be that the pathogenesis and metastasis mechanism of osteosarcoma remains unclear.So,it is crucial to reveal its molecular mechanisms and develop new and valid targeted therapy of osteosarcoma.Firstly,we applied neogambogic acid(NGA),extracted from traditional Chinese medicine garcinia in our previous study,and explored its anti-tumor effects in osteosarcoma cells.Next,through CETSA assay,we demonstrated that deubiquitinase USP9 x might be a target of NGA.Finally,we revealed the related mechanism of USP9 x in osteosarcoma.We discovered that neogambogic acid(NGA)was able to exert significant anti-tumor effects in osteosarcoma.It inhibited the proliferation,induced apoptosis,resisted the cell cycle and reduced the colony formation in osteosarcoma cells.Next,we demonstrated that deubiquitinase USP9 x might be a target of NGA,and that reducing the expression of USP9 x might suppress the cell proliferation and metastasis in osteosarcoma,through stimulating the degradation of SOX2.All the results showed that NGA might be a promising chemotherapeutic drug which accelerated the degradation of SOX2 by targeting USP9 x in osteosarcoma.All together,these findings could shed a light on the targeted therapy of osteosarcoma.USP 14,a deubiquitinating enzyme related to the ubiquitin-proteasome system,has been implicated in the tumorigenesis and progression of several cancers,but its role in oral squamous cell carcinoma(OSCC)remains to be elucidated.Firstly,we found that USP 14 was overexpressed in oral cancer tissues and cell lines at both mRNA and protein levels.Also,specific inhibition of its enzyme activity with b-AP15,or knockdown by shRNA significantly inhibit the growth of cancer cells and induced cell apoptosis in vitro.Collectively,USP14 could be a potential therapeutic target for OSCC patients.All these study will succeed in providing more accurate and reliable information for targeted therapy and new drug research of OSCC.