mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A

Abstract

Background Exploiting cancer metabolism during nutrient availability holds immense potential for the clinical and therapeutic benefits of hepatocellular carcinoma (HCC) patients. Dietary methionine is a metabolic dependence of cancer development, but how the signal transduction integrates methionine status to achieve the physiological demand of cancer cells remains unknown. Methods Low or high levels of dietary methionine was fed to mouse models with patient-derived xenograft or diethyl-nitrosamine induced liver cancer. RNA sequence and metabolomics were performed to reveal the profound effect of methionine restriction on gene expression and metabolite changes. Immunostaining, sphere formation assays, in vivo tumourigenicity, migration and self-renewal ability were conducted to demonstrate the efficacy of methionine restriction and sorafenib. Results We discovered that mTORC1-c-Myc-SIRT4 axis was abnormally regulated in a methionine-dependent manner and affected the HCC progression. c-Myc rewires methionine metabolism through TRIM32 mediated degradation of SIRT4, which regulates MAT2A activity by ADP-ribosylation on amino acid residue glutamic acid 111. MAT2A is a key enzyme to generate S-adenosylmethionine (SAM). Loss of SIRT4 activates MAT2A, thereby increasing SAM level and dynamically regulating gene expression, which triggers the high proliferation rate of tumour cells. SIRT4 exerts its tumour suppressive function with targeted therapy (sorafenib) by affecting methionine, redox and nucleotide metabolism. Conclusions These findings establish a novel characterization of the signaling transduction and the metabolic consequences of dietary methionine restriction in malignant liver tissue of mice. mTORC1, c-Myc, SIRT4 and ADP ribosylation site of MAT2A are promising clinical and therapeutic targets for the HCC treatment.

CoCl2‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

“…However, this mechanism may not be relevant under (pseudo)hypoxic conditions given that hypoxia downregulates TRIM32 protein levels as shown in pulmonary artery smooth muscle cells [61]. Thus, it remains to be determined (a) whether other SIRT4 interacting E3-Ubiquitin protein ligases, including RNF138 [60] or TRIM28 ( [60] and own unpublished results), are involved in proteasomal degradation of SIRT4, and (b) which of the lysine residues K78 and K299 are targeted by these E3-Ubiquitin ligases. Overall, our findings indicate that lysine K78 regulates protein half-life under basal conditions (Fig.…”

Advances of SIRT4 in cancer metabolism and therapy

“…39 A recent study found that SIRT4 can inhibit methionine metabolism via MAT2A methylation, inhibiting hepatocellular carcinoma progression. 41 As mentioned above, SIRT4 not only regulates glutamine metabolism in tumors but is also involved in regulating valine, leucine, isoleucine, and methionine metabolism.…”

“…In a pancreatic ductal adenocarcinoma (PDAC) study, SIRT4 deacetylated branched‐chain amino acid transaminase 2 (BCAT2) at lysine 44 (K44), and BCAT2 was stabilized by SIRT4 deacetylation, thereby promoting catabolism of branched‐chain amino acids, 40 whereas methylcrotonyl coenzyme A carboxylase complex (MCCC) was previously shown to interact with SIRT4 and was considered a putative substrate for SIRT4 39 . A recent study found that SIRT4 can inhibit methionine metabolism via MAT2A methylation, inhibiting hepatocellular carcinoma progression 41 . As mentioned above, SIRT4 not only regulates glutamine metabolism in tumors but is also involved in regulating valine, leucine, isoleucine, and methionine metabolism.…”

“…Doxorubicin (DOX) is an effective anthracycline‐based chemotherapeutic agent. However, its induced cardiotoxicity (DIC) limits its application in cancer therapy, and one study found that SIRT4 overexpression can inhibit Akt/mTOR‐dependent autophagy from preventing DIC 57 ; in the antitumor aspect of herbal medicine, it was found that paeoniflorin can inhibit STAT3 activation and prevent DIC by promoting SIRT4 expression to enhance the sensitivity of estrogen receptor‐positive breast cancer cells to tamoxifen; Sorafenib is a first‐line dual‐target inhibitor that can target both serine‐threonine kinase Raf and tyrosine kinase VEGFR/PDGFR, while SIRT4 can synergize with sorafenib to make hepatocellular carcinoma cells more sensitive to sorafenib‐targeted therapy by inhibiting methionine metabolism 41 . In conclusion, these results highlight the potential application of SIRT4 in cancer therapy.…”

Combination of Everolimus and Bortezomib Inhibits the Growth and Metastasis of Bone and Soft Tissue Sarcomas via JNK/p38/ERK MAPK and AKT Pathways

“…mTORC1 signaling regulates a variety of metabolic pathways by activating transcription factors, including the oncogenic transcription factor MYC. mTORC1 activates MYC to promote hepatocellular carcinoma tumorigenesis by modulating methionine metabolism [54]. MYC can provide an advantage to cancer cells by promoting proliferation and angiogenesis, helping to evade the immune response [55].…”