c‐Myc–IMPDH1/2 axis promotes tumourigenesis by regulating GTP metabolic reprogramming

Abstract

Background Metabolic reprogramming is a hallmark of cancer. Metabolic rate‐limiting enzymes and oncogenic c‐Myc (Myc) play critical roles in metabolic reprogramming to affect tumourigenesis. However, a systematic assessment of metabolic rate‐limiting enzymes and their relationship with Myc in human cancers is lacking. Methods Multiple Pan‐cancer datasets were used to develop the transcriptome, genomic alterations, clinical outcomes and Myc correlation landscapes of 168 metabolic rate‐limiting enzymes across 20 cancers. Real‐time quantitative PCR and immunoblotting were, respectively, used to examine the mRNA and protein of inosine monophosphate dehydrogenase 1 (IMPDH1) in human colorectal cancer (CRC), azoxymethane/dextran sulphate sodium‐induced mouse CRC and spontaneous intestinal tumours from APC Min/+ mice. Clone formation, CCK‐8 and subcutaneous xenograft model were applied to investigate the possible mechanisms connecting IMPDH1 to CRC growth. Co‐immunoprecipitation and protein half‐life assay were used to explore the mechanisms underlying the regulation of IMPDH1. Results We explored the global expression patterns, dysregulation profiles, genomic alterations and clinical relevance of 168 metabolic rate‐limiting enzymes across human cancers. Importantly, a series of enzymes were associated with Myc, especially top three upregulated enzymes (TK1, RRM2 and IMPDH1) were positively correlated with Myc in multiple cancers. As a proof‐of‐concept exemplification, we demonstrated that IMPDH1, a rate‐limiting enzyme in GTP biosynthesis, is highly upregulated in CRC and promotes CRC growth in vitro and in vivo. Mechanistically, IMPDH2 stabilizes IMPDH1 by decreasing the polyubiquitination levels of IMPDH1, and Myc promotes the de novo GTP biosynthesis by the transcriptional activation of IMPDH1/2. Finally, we confirmed that the Myc–IMPDH1/2 axis is dysregulated across human cancers. Conclusions Our study highlights the essential roles of metabolic rate‐limiting enzymes in tumourigenesis and their crosstalk with Myc, and the Myc–IMPDH1/2 axis promotes tumourigenesis by altering GTP metabolic reprogramming. Our results propose the inhibition of IMPDH1 as a viable option for cancer treatment.

The IMPDH cytoophidium couples metabolism and fetal development in mice

“…Recently, the significance of elevated IMPDH levels in proliferative cells has been depicted in several studies. In various human cancers, the interplay between c-Myc and IMPDH has been demonstrated to regulate GTP metabolic reprogramming during tumorigenesis [ 41 ]. Elevated GTP production in human glioblastoma is essential for supporting rRNA and tRNA synthesis [ 42 ].…”

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

“…IMPDH2 is commonly upregulated in malignancies [ 39 ] including primary CRC [ 40 ]. IMPDH2 has been shown to promote CRC tumorigenesis [ 41 ], metastatic potential [ 42 ] and in methotrexate resistance [ 43 ]. Thus, IMPDH2 has been previously implied as a potential prognostic marker for CRC outcomes and may be useful as a drug target.…”

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers

“…The guanosine biosynthetic enzymes, inosine monophosphate dehydrogenases (IMPDHs), are frequently upregulated by MYC in cancers. Since IMPDHs are rate-limiting enzymes, their blocking via mizoribine effectively reduces ribosome biogenesis and GTP biosynthesis in small cell lung cancer [ 183 , 184 ].…”