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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: Mesenteric adipose tissue (MAT) in Crohn’s disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long-term outcomes. These findings indicate that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in CD-MAT, but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. This study aimed to characterize CD-MAT-specific bacteria and explore their roles in promoting intestinal inflammation. Methods We utilized 16S rRNA gene sequencing and culture-omics to characterize the translocated viable bacteria in MAT from CD. The pro-inflammatory role of the identified candidate bacteria was examined using a co-culture assay in vitro and in a colitis mouse model in vivo. The type VI secretion system (T6SS) is thought to promote the pro-inflammatory effect, and a CRISPR interference system was employed to knockdown a core gene expression in T6SS. Results We report that members of Enterobacteriaceae were enriched in CD-MAT compared with non-CD controls. Viable Klebsiella variicola in Enterobacteriaceae was identified exclusively in CD-MAT, which induces a pro-inflammatory response in vitro and exacerbates colitis in mice. This is the first evidence that colitogenic K. variicola exists in the mesenteric tissue. Active T6SS was found in the K. variicola genome, which could impair the intestinal barrier by inhibiting the ZO-1 expression. Dysfunction of T6SS alleviated the inhibitory effect of K. variicola on ZO-1 expression and attenuated colitis in mice. Importantly, we validated that K. variicola and T6SS were enriched in the gut microbiome of patients with CD, further confirming that they are closely related to the occurrence of CD. Conclusions CD mesenteric adipose tissue-derived K. variicola can disrupt the intestinal barrier and promote intestinal colitis induced by T6SS.

BackgroundPrevious study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed.MethodsIn this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes.ResultsWe found that, MMP1, MMP3, MMP7, MMP9–MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time.DiscussionThis study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.