Metabolic reprogramming is a hallmark of cancer. However, it is not well known how metabolism affects cancer progression. We identified that metabolic enzyme acyl-CoA oxidase 1 (ACOX1) suppresses colorectal cancer (CRC) progression by regulating palmitic acid (PA) reprogramming. ACOX1 is highly downregulated in CRC, which predicts poor clinical outcome in CRC patients. Functionally, ACOX1 depletion promotes CRC cell proliferation in vitro and colorectal tumorigenesis in mouse models, whereas ACOX1 overexpression inhibits patient-derived xenograft growth. Mechanistically, DUSP14 dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation, thereby leading to an increase of the ACOX1 substrate PA. Accumulated PA promotes β-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of β-catenin and subsequent β-Trcp-mediated proteasomal degradation. In return, stabilized β-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of β-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-β-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated β-catenin palmitoylation and stabilization and hyperactivates β-catenin signaling thus promoting CRC progression. Particularly, targeting β-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit β-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-β-catenin axis by Nu-7441 reduced the viability of CRC cells. Our results reveal an unexpected role of PA reprogramming induced by dephosphorylation of ACOX1 in activating β-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or β-catenin palmitoylation as a viable option for CRC treatment.

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.

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