As a common tumor of the urinary system,the morbidity and mortality related to renal carcinoma,are increasing annually.Clear cell renal cell carcinoma(CCRCC)is the most common subtype of renal cell carcinoma,accountin...As a common tumor of the urinary system,the morbidity and mortality related to renal carcinoma,are increasing annually.Clear cell renal cell carcinoma(CCRCC)is the most common subtype of renal cell carcinoma,accounting for approximately 75%of the total number of patients with renal cell carcinoma.Currently,the clinical treatment of ccRCC involves targeted therapy,immunotherapy,and a combination of the two.In immunotherapy,PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment.However,as treatment progresses,some patients gradually develop resistance to immunotherapy.Meanwhile,other patients experience great side effects after immunotherapy,resulting in a survival status far lower than the expected survival rate.Based on these clinical problems,many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results.We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.展开更多
Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its fun...Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism.HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock - in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branchedchain amino acids catabolism, and reduced muscle mass during aging, without changes in the muscle fiber-type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance.展开更多
基金The Ph.D.Start-Up Fund of Liaoning Province from GW(2021-BS-209,Liaoning Province,30000 CNY)Natural Science Foundation of Liaoning Province of China(2021-MS-278,Liaoning Province,100000 CNY).
文摘As a common tumor of the urinary system,the morbidity and mortality related to renal carcinoma,are increasing annually.Clear cell renal cell carcinoma(CCRCC)is the most common subtype of renal cell carcinoma,accounting for approximately 75%of the total number of patients with renal cell carcinoma.Currently,the clinical treatment of ccRCC involves targeted therapy,immunotherapy,and a combination of the two.In immunotherapy,PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment.However,as treatment progresses,some patients gradually develop resistance to immunotherapy.Meanwhile,other patients experience great side effects after immunotherapy,resulting in a survival status far lower than the expected survival rate.Based on these clinical problems,many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results.We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.
文摘Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism.HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock - in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branchedchain amino acids catabolism, and reduced muscle mass during aging, without changes in the muscle fiber-type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance.
