The GOLM1-ACLY pathway regulates macrophage-secreted EFEMP1 via H3K27ac modifications to drive tumor progression

BACKGROUND: Macrophages play crucial regulatory roles within the tumor immune microenvironment (TIME) and significantly influence tumor progression. GOLM1 has been identified as being closely associated with a variety of cancers. Nevertheless, the role of GOLM1 in macrophages on tumor progression remains unknown. OBJECTIVES: This study aims to investigate the mechanism by which the GOLM1-ACLY axis in macrophages regulates tumor progression. METHODS: The orthotopic hepatocellular carcinoma (HCC) inoculationand subcutaneous tumor implantation were used to establish mouse tumor models. The expression levels of the indicated proteins were assessed by immunohistochemistry and immunoblotting. Coimmunoprecipitation (Co-IP), mass spectrometry (MS), and immunofluorescence were employed to determine the interactions between proteins. Bulk RNA sequencing was used to explore the mRNA profiles in bone marrow-derived monocytes (BMDMs). Moreover, qPCR was used to quantify the mRNA levels. CUT&Tag sequence and qPCR assays were performed to assess the DNA sequences bound by H3K27ac. RESULTS: We identified that GOLM1 was observed to be markedly upregulated in macrophages from both liver/lung cancer patients and mouse tumor models. Macrophage deletion of GOLM1 suppressed tumor proliferation and provoked metabolic reprogramming in tumor cells. IP-MS analysis identified the Adenosine triphosphate citrate lyase (ACLY) protein as an interacting partner of GOLM1. Mechanistically, GOLM1 could bind to ACLY and impede the phosphorylation of ACLY by protein kinase A (PKA). The knockout of GOLM1 significantly increased the P-ACLY level in the nucleus of macrophage. Specifically, elevated P-ACLY significantly promoted monoacetylation at lysine 27 of histone H3 (H3K27ac). Combined analysis of CUT&Tag-seq and RNA-seq date further revealed a notable decrease of H3K27ac levels in the EFEMP1 gene, which promoted tumor proliferation via EGFR-MAPK/AKT signaling Genetic or pharmacological intervention via Acly-targeted siRNA or the ACLY inhibitor known as bempedoic acid (BA) abolished the tumor-suppressive effect induced by macrophage-specific GOLM1 deletion. CONCLUSIONS: Our findings reveal a novel mechanism involving the GOLM1-ACLY axis within macrophages that regulates tumor progression, which suggest a potential strategy for tumor intervention.