Lipid metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Lipid accumulation affects cellular energy homeostasis, biofilm synthesis, lipid signal transduction, and phenotypic transformation in ccRCC. Herein, a prognostic‐related model was constructed, and the prognostic utility of AUP1, a lipid droplet–regulating very low–density lipoprotein assembly factor, in ccRCC was determined through multiparameter analysis. AUP1 expression was significantly higher in clinical samples than in normal tissues and was closely associated with the clinical stage. The inhibition of AUP1 expression impaired the proliferation, migration, and invasion of ACHN and A498 ccRCC cells in vitro and in vivo. RNA‐seq analysis revealed that AUP1 inhibition can significantly reduce the contents of intracellular triglyceride and cholesterol and regulate cell growth by cell cycle arrest, promoting apoptosis and reversing epithelial‐mesenchymal transition. AUP1 regulated the synthesis of cholesterol esters and fatty acids (FAs) in ccRCC cells by targeting sterol O‐acyltransferase 1 and partially promoted the progression of ccRCC. AUP1 also induced lipid accumulation in ccRCC by promoting the de novo synthesis of FAs (inhibiting protein kinase AMP‐activated catalytic subunit alpha 2), inhibiting the rate‐limiting enzyme of FA β oxidation (carnitine palmitoyltransferase 1A), regulating the key enzyme of lipolysis (monoglyceride lipase, MGLL), and inhibiting the lipid transporter StAR‐related lipid transfer domain containing 5 (STARD5). However, it did not affect the intracellular cholesterol synthesis pathway. The differential expression and prognostic significance of MGLL and STARD5 in ccRCC should be further studied. AUP1 may serve as a new and effective potential target and prognostic marker for ccRCC.
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with high metastatic and invasive nature. Super enhancers (SEs) control the expression of cell identity genes and oncogenes during tumorigenesis. As a glycosaminoglycan in the tumor microenvironment, hyaluronan (HA) is associated with cancer development. High expression of hyaluronan synthase 3 (HAS3) resulted in HA deposition, which promoted the growth of cancer cell. However, its role in NPC development remains elusive. We demonstrated that the levels of HAS3 mRNA or protein were increased in NPC cell lines. Transcription of HAS3 is associated with SE. Disruption of SE by bromodomain containing 4 (BRD4) inhibitor JQ1 resulted in downregulation of HAS3 and inhibition of cell proliferation and invasiveness in NPC cells. Inhibition of HA synthesis by HAS inhibitor 4-MU suppressed cell growth and invasion of NPC cells, whereas HA treatment exerted opposite effects. Genetically silencing HAS3 in HK1 and FaDu NPC cells attenuated cell proliferation and mobility, while re-expression of HAS3 enhanced malignant potential of CNE1 and CNE2 NPC cells. Furthermore, loss of HAS3 impaired metastatic potential of HK1 cells in nude mice. Mechanistically, inhibition of HA synthesis by chemical inhibitor or silencing HAS3 led to reduction of the levels of phosphorylation of EGFR, AKT, and ERK proteins. In contrast, exogenous HA treatment or forced expression of HAS3 activated EGFR/AKT/ERK signaling cascade. This study suggested that HAS3 is driven by SE and overexpressed in NPC. High expression of HAS3 promotes the malignant features of NPC via activation of EGFR/AKT/ERK signaling pathway.
Purpose Nasopharyngeal carcinoma (NPC) is an aggressive head and neck disease with a high incidence of distant metastases. Enlargeosomes are cytoplasmic organelles marked by, desmoyokin/AHNAK. The purpose of this study was to evaluate the expression of AHNAK in NPC and its effect on enlargeosomes, and to investigate the correlation between AHNAK expression levels and clinical NPC patient characteristics. Methods Primary nasopharyngeal carcinoma (NPC) and NPC specimens were evaluated by analyzing public data, immunohistochemistry. Systematic in vitro and in vivo experiments were performed using different NPC-derived cell lines and mouse models. Results In this study, we detected AHNAK and Annexin A2(ANXA2), a protein coating the surface of enlargeosomes, in NPC samples. We found that AHNAK was down-regulated, whereas Annexin A2 was upregulated in human NPC tissues. Down-regulation of AHNAK was associated with poor overall survival in NPC patients. Upregulation of Annexin A2 was associated with lymph node metastasis and distant metastasis in NPC patients. Functional studies confirmed that silencing of AHNAK enhanced the growth, invasion, and metastatic properties of NPC cells both in vitro and in vivo. In terms of mechanism, loss of AHNAK led to increase of annexin A2 protein level in NPC cells. Silencing ANXA2 restored the migrative and invasive ability of NPC cells upon loss of AHNAK. Moreover, transcription factor FOSL1-mediated transcriptional repression was responsible for the low-expression of AHNAK by recruiting EZH2. Conclusion Here, we report AHNAK as a tumor suppressor in NPC, which may act through annexin A2 oncogenic signaling in enlargeosome, with potential implications for novel approaches to NPC treatment.
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