Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

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 beta-catenin cysteine 466 palmitoylation, which inhibits CK1- and GSK3-directed phosphorylation of beta-catenin and subsequent beta-Trcp-mediated proteasomal degradation. In return, stabilized beta-catenin directly represses ACOX1 transcription and indirectly activates DUSP14 transcription by upregulating c-Myc, a typical target of beta-catenin. Finally, we confirmed that the DUSP14-ACOX1-PA-beta-catenin axis is dysregulated in clinical CRC samples. Together, these results identify ACOX1 as a tumor suppressor, the downregulation of which increases PA-mediated beta-catenin palmitoylation and stabilization and hyperactivates beta-catenin signaling thus promoting CRC progression. Particularly, targeting beta-catenin palmitoylation by 2-bromopalmitate (2-BP) can efficiently inhibit beta-catenin-dependent tumor growth in vivo, and pharmacological inhibition of DUSP14-ACOX1-beta-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 beta-catenin signaling and promoting cancer progression, and propose the inhibition of the dephosphorylation of ACOX1 by DUSP14 or beta-catenin palmitoylation as a viable option for CRC treatment.

Automated summary

Metabolic enzyme ACOX1 suppresses colorectal cancer progression by regulating palmitic acid reprogramming. ACOX1 is highly downregulated in CRC, and its depletion promotes cell proliferation and tumor growth while overexpression inhibits tumor growth. DUSP14 dephosphorylates ACOX1, leading to increased levels of ACOX1 substrate palmitic acid.