| Among primary liver cancers,hepatocellular carcinoma(HCC)is the major histological subtype and accounts for 70-85%of total liver cancer cases.It is characterized by high degree of malignancy,difficult treatment,poor prognosis and easy recurrence and metastasis.The high mortality rate of HCC is closely related to the lack of appropriate biomarkers for early detection,the insufficient understanding of HCC heterogeneity as well as the treatment resistance.Cancer stem cells(CSCs)are a small group of cells which normally expressed progenitor cell markers,highly tumorigenic/metastatic,and resistant to radiation and chemotherapy.Based on these characteristics,CSCs are considered to be an extremely important factor to cause tumor heterogeneity,tumor recurrence,metastasis,and drug resistance.Therefore,the identification of new CSCs-specific molecular markers for HCC and the regulatory mechanisms in the process of proliferation and differentiation of HCC cells are of great importance for the prevention and therapy of HCC.MYC is one of the most famous oncogenes in human cancer.It can not only induce the conversion of normal cells into malignant cells,but also promotes the escape of cancer cells from immune response,which is closely related to tumor recurrence,metastasis and drug resistance.In addition,MYC is a key stem cell regulator,which could reprogram adult hepatocytes into pluripotent stem cells.The post-translational modifications of MYC,such as phosphorylation,ubiquitination and acetylation,regulates its transcriptional activity by affecting the formation of MYC transcription complexes or proteasome degradation.Therefore,targeting MYC,especially in combination with traditional therapies for liver cancer,has been considered as a potential therapeutic strategy for HCC.The different metabolic pathways play an crucial role for sustaining their proliferation,growth,invasion and migration of tumor cells.In this study,we used the CRISPR/Cas9 metabolic library and explored the biological mechanism of SCARB2 maintaining the characteristics of CSCs and driving the initiation and progression of hepatocellular carcinoma.We found that deletion of SCARB2 suppressed the progression and incidence of liver cancer in a spontaneous mouse model of liver cancer.Mechanistically,binding of SCARB2 with MYC promoted MYC acetylation by interfering with HDCA3-mediated MYC deacetylation and subsequently enhanced MYC transcriptional activity.Polymyxin B displayed high binding affinity for SCARB2 protein,disrupted the SCARB2-MYC interaction,decreased MYC transcriptional activity,and reduced the tumor burden.Our study identifies SCARB2 as a marker and functional driver of HCC CSCs and suggests a targeted therapeutic option for HCC.We generated pharmacophore models of ULK1 based on the X-ray structure of UKL1 in complex with ligands.We then screened the Specs chemical library based on the pharmacophore 6QAS、5CI7 and 4WNO for potential UKL1 inhibitors.By molecular docking,we screened out the 19 compounds among 21K compounds through structurebased virtual screening.Through CCK8 activity screening and SPR assay,we found that ZZY-19 displayed a higher binding affinity for ULK1.Moreover,ZZY-19 also performed well anti-HCC activities.Especially,ZZY-19 induces autophagy inhibition by reducing the expression of the ULK1.The combination of ZZY-19 with sorafenib synergistically suppressed the progression of HCC in vivo.Taken together,ZZY-19 was potential candidate compound targeting ULK1 and possessing anti-HCC activities by inhibiting autophagy.In conclusion,our study identified SCARB2 as a positive molecular marker of HCC,which is involved in maintaining tumor stem cell-like traits and promoting the occurrence of HCC.The ULK1 specific inhibitor,ZZY-19,suppresses the progression of HCC by inhibiting autophagy.Our study provides theoretical and experimental basis for the application of small molecule combined with sorafenib therapy strategy in the treatment of HCC. |
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