Fig. 8

Myc promoted SIRT4 degradation to reduce ADP ribosylation of MAT2A in the HCC. A Protein levels of c-Myc, MAT2A and MARylation level of MAT2A were determined by western blot from 85 pairs of tumour tissues. In the inserted boxplots, the circles indicate the median; the square indicate the 5th–95th percentiles. The statistical analysis was performed by the two tailed Student’s t-test (**p < 0.01). B Correlation between Myc and SIRT4 in HCC patients. 85 tissue pairs were immunohistochemically stained with indicated antibodies. The pair-wise Pearson correlation coefficient and the corresponding p-value between two genes were calculated. C The patients with high SIRT4 expression (n = 43) have longer survival compared to low SIRT4 expression (n = 42). Significance was determined using Kaplan–Meier analysis. D Schematic showing that high methionine content is sensed by mTORC1 that triggers c-Myc expression, which promotes TRIM32-mediated SIRT4 degradation. SIRT4 regulates MAT2A activity through MARylation, thereby inhibits MAT2A mediated tumour growth. SIRT4 loss resulted in the low MARylation level of MAT2A, which promotes methionine metabolism to generate SAM. In a feedback, high SAM level triggers transcription of metabolic enzymes to maintain tumour progression. Upward pointing arrows indicate an increase, and downwards pointing arrows indicate a decrease