Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression.

Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.

Clinical Significance of Acylphosphatase 1 Expression in Combined HCC-iCCA, HCC, and iCCA.

BACKGROUND: Combined hepatocellular and cholangiocarcinoma is a rare primary liver cancer with histological features of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Little is known about the prognostic features and molecular mechanism of cHCC-iCCA. Acylphosphatase 1 is a cytosolic enzyme that produces acetic acid from acetyl phosphate and plays an important role in cancer progression. AIMS: We evaluated the clinical significance of ACYP1 expression in cHCC-iCCA, HCC, and iCCA. METHODS: ACYP1 immunohistochemistry was performed in 39 cases diagnosed with cHCC-iCCA. The prognosis was evaluated in three different cohorts (cHCC-iCCA, HCC, and iCCA). The relationships between ACYP1 expression and cell viability, migration, invasiveness, and apoptosis were examined using siRNA methods in vitro. In vivo subcutaneous tumor volumes and cell apoptosis were evaluated after downregulation of ACYP1 expression. RESULTS: Almost half of the patients with cHCC-iCCA were diagnosed with high ACYP1 expression. In all three cohorts, the cases with high ACYP1 expression had significantly lower overall survival, and high ACYP1 expression was identified as an independent prognostic factor. Downregulation of ACYP1 reduced the proliferative capacity, migration, and invasiveness of both HCC and iCCA cells. Moreover, knockdown of ACYP1 increased the ratio of apoptotic cells and decreased the expression of anti-apoptosis proteins. In vivo tumor growth was significantly inhibited by the transfection of ACYP1 siRNA, and the number of apoptotic cells increased. CONCLUSION: High ACYP1 expression could influence the prognosis of cHCC-iCCA, HCC, and iCCA patients. In vitro ACYP1 expression influences the tumor growth and cell viability in both HCC and iCCA by regulating anti-apoptosis proteins.

ACYP1 Is a Pancancer Prognostic Indicator and Affects the Immune Microenvironment in LIHC.

Background: ACYP1 plays important physiological and metabolic roles in glycolysis and membrane ion pump activity by catalyzing acyl phosphate hydrolysis. ACYP1 is related to tumorigenesis and progression and poor prognosis in gastrointestinal cancer. However, its pancancer roles and mechanisms are unclear. Our study aimed to understand the ACYP1 expression signature and prognostic value across cancers and investigate immune infiltration patterns in liver hepatocellular carcinoma (LIHC) and verify them in LIHC samples. Methods: Transcriptional expression profiles of ACYP1 across cancers were analyzed using Oncomine and TIMER. The prognostic value of ACYP1 was assessed across PrognoScan, Kaplan-Meier Plotter, and GEPIA. Significant pathways associated with ACYP1 in LIHC were obtained via Gene Set Enrichment Analysis. The correlation between ACYP1 expression and immune infiltration in LIHC was investigated using TIMER. We validated ACYP1 expression, prognostic value, and association with immune cells in tumor tissues by immunohistochemistry and flow cytometry. Results: ACYP1 was overexpressed across cancers. High expression of ACYP1 correlated with a poor prognosis in most tumor types, especially in LIHC. ACYP1 was significantly implicated in immune and metabolic related pathways. High ACYP1 expression showed significant correlations with the abundances of Th2 cells, Tregs, macrophages, dendritic cells, and myeloid-derived suppressor cells in LIHC. LIHC patients with high ACYP1 expression showed significantly shorter overall survival and relapse-free survival rates concomitant with increased infiltration of CD4+ T cells. Mouse subcutaneous tumors with ACYP1 overexpression exhibited significantly accelerated tumor progression with increased aggregation of CD4+ T cells. Conclusion: Overall, ACYP1 may serve as a vital prognostic biomarker and play an immunoregulatory role in LIHC.