Long noncoding RNA RHPN1-AS1 promotes hepatocellular carcinoma progression under hypoxia through interaction with RPS15A protein.

Abstract

Hypoxic microenvironment is a hallmark feature of hepatocellular carcinoma (HCC) and contributes to cancer progression. RHPN1-AS1, a long noncoding RNA (lncRNA), plays an important role in multiple cancers. However, its expression and oncogenic function under hypoxic conditions have not yet been determined. In this study, we investigated the expression changes of RHPN1-AS1 in HCC cells upon hypoxia. The effects of RHPN1-AS1 knockdown and overexpression on hypoxic HCC cells were explored. The protein partner involved in RHPN1-AS1 action in hypoxic HCC cells was characterized. We found that exposure to hypoxia led to an increase in the RHPN1-AS1 level in HCC cells, which was blocked by depletion of HIF-1α. Chromatin immunoprecipitation assay revealed the enrichment of HIF-1α at the promoter of RHPN1-AS1 in hypoxic HCC cells. Knockdown of RHPN1-AS1 suppressed HCC cell proliferation, colony formation, and invasion under hypoxia, whereas overexpression of RHPN1-AS1 promoted the proliferation and invasion of hypoxic HCC cells. Mechanistically, RHPN1-AS1 interacted with and stabilized RPS15A protein in hypoxic HCC cells. Elevated expression of RPS15A protein enhanced the proliferation and invasion of hypoxic HCC cells through activation of β-catenin signaling. Silencing of RPS15A attenuated RHPN1-AS1-induced aggressiveness and β-catenin activation in hypoxic HCC cells. In vivo tumorigenic studies confirmed that RPS15A depletion significantly reduced the growth of RHPN1-AS1-overexpressing HCC xenograft tumors. RHPN1-AS1 serves as a hypoxia-responsive lncRNA and interacts with the RPS15A protein partner to activate the β-catenin pathway, consequently enhancing HCC progression under hypoxia.