Purine anabolism creates therapeutic vulnerability in hepatocellular carcinoma through m6A-mediated epitranscriptomic regulation

Abstract

Background and Aims: Purines are building blocks for the cellular genome, and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumors, and impacting tumorigenesis remains elusive. Approach and Results: Transcriptomic and metabolomic analyses of purine biosynthesis and purine degradation pathways were performed in the tumor and associated nontumor liver tissues obtained from 62 patients with HCC, one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated, while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DNA damage repairing (DDR) machinery through upregulating RNA N6-methyladenosine (m6A) modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in 5 independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo. Conclusions: Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.

Effects of N6-methyladenosine modification on metabolic reprogramming in digestive tract tumors

“…Studies highlight the involvement of aberrant expression of m6A-related molecules, such as regulatory enzymes, binding proteins, and target RNAs, in the regulation of the metabolic dynamics of tumor cells [ [88] , [89] , [90] , [91] , [92] ]. Increasing lines of evidence have uncovered that m6A modifications regulate the expression and stability of key metabolism-related genes, thereby contributing to the metabolic reprogramming observed in digestive tract tumors [ [93] , [94] , [95] , [96] , [97] ] ( Table 1 ) . The following sections will focus on summarizing the mechanism underlying m6A’s regulatory influence on tumor metabolism with respect to the three types of m6A effector molecules, including m6A methyltransferases, demethylases, and binding proteins ( Fig.…”

“… Disease Metabolism Writer Eraser Reader Related targets a Underlying mechanism in tumor metabolism b Refs. liver cancer glucose metabolism METTL3 / / HIF-1α mRNA HBXIP-mediated METTL3 overexpression increased HIF-1α level [ 88 ] glucose metabolism METTL14 / / USP48 mRNA METTL14 maintained USP48 mRNA stability to inhibit SIRT6 degradation [ 89 ] glucose metabolism ZC3H13 / / PKM2 mRNA ZC3H13-induced m6A-modified patterns abolished PKM2 mRNA stability [ 90 ] lipid metabolism METTL3, and METTL14 / / ACLY, and SCD1 mRNA METTL14 and METTL3 directly increased the m6A modification of ACLY and SCD1 mRNA [ 91 ] lipid metabolism METTL5 / / 18S rRNA METTL5 mediated 18S rRNA m6A modification to upregulate the mRNA translation of ACSL4 [ 92 ] purine anabolism METTL3 / / DTL mRNA METTL3 upregulated the m6A modification of DTL [ 93 ] glucose metabolism / ...…”

“… Disease a m6A regulators Metabolism Role in diseases Year Refs. HCC METTL3 glucose metabolism Carcinogenic effects 2021 [ 88 ] METTL14 glucose metabolism Anti-cancer effects 2021 [ 89 ] ZC3H13 glucose metabolism Anti-cancer effects 2021 [ 90 ] ALKBH5 glucose metabolism Anti-cancer effects 2022 [ 105 ] YTHDF3 glucose metabolism Carcinogenic effects 2022 [ 112 ] IGF2BP2 glucose metabolism Carcinogenic effects 2023 [ 113 ] METTL3, and METTL14 lipid metabolism Carcinogenic effects 2022 [ 91 ] METTL5 lipid metabolism Carcinogenic effects 2022 [ 92 ] METTL3 purine anabolism Carcinogenic effects 2023 [ 93 ] …”

“…Furthermore, METTL3 was demonstrated to upregulate DTL (a substrate receptor associated with the Cullin4-ring E3 ubiquitin ligase complex), thereby facilitating purine anabolism and contributing to adverse clinical outcomes in HCC ( Fig. 2 ) [ 93 ].

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KIAA1429 facilitates progression of hepatocellular carcinoma by modulating m6A levels in HPN

“…m6A RNA methylation is involved in various biological processes, including stem cell formation and differentiation [ 11 ], transcription, translation, embryogenesis, nuclear export, alternative splicing, heat shock response control [ 12 ], circadian clock control [ 13 ], DNA damage response, and degradation of mRNAs [ [14] , [15] , [16] , [17] , [18] ]. Studies have suggested that abnormal m6A RNA methylation plays a vital role in the pathogenesis of diverse human diseases such as LIHC [ [19] , [20] , [21] , [22] , [23] , [24] ]. For example, WTAP methylation by PRMT1 promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NADH:ubiquinone oxidoreductase subunit S6 (NDUFS6) [ 25 ].…”