Long noncoding RNA LINC01234 promotes hepatocellular carcinoma progression through orchestrating aspartate metabolic reprogramming

Abstract

Amino acids metabolism, especially aspartate metabolism, is often altered in human cancers including hepatocellular carcinoma (HCC) and this metabolic remodeling is required for supporting cancer cell malignant activities. Argininosuccinate synthase 1 (ASS1), as a crucial rate-limiting enzyme in aspartate metabolism, participates in repressing tumor progression. However, the roles of long noncoding RNAs (lncRNAs) in aspartate metabolism remodeling and the underlying mechanisms remain unclear. Here, we screen LINC01234 as an aspartate metabolism-related lncRNA in HCC. Clinically, LINC01234 was highly expressed in HCC, and a high LINC01234 expression level was correlated with a poor prognosis of patients with HCC. LINC01234 promoted cell proliferation, migration, and drug resistance by orchestrating aspartate metabolic reprogramming in HCC cells. Mechanistically, LINC01234 downregulated the expression of ASS1, leading to am increased aspartate level and activation of the mammalian target of rapamycin pathway. LINC01234 bound to the promoter of ASS1 and inhibited transcriptional activation of ASS1 by transcriptional factors, including p53. Finally, inhibiting LINC01234 dramatically impaired tumor growth in nude mice and sensitized HCC cells to sorafenib. These findings demonstrate that LINC01234 promotes HCC progression by modulating aspartate metabolic reprogramming and might be a prognostic or therapeutic target for HCC.

Keywords: ASS1; LINC01234; hepatocellular carcinoma; metabolic reprogramming; p53.