Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/beta-catenin signaling to promote colorectal cancer progression by preventing m(6)A-mediated degradation of STEAP3 mRNA

Background: Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined. Methods: The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1 alpha. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/beta-catenin axis in CRC proliferation and metastasis. Results: Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1 alpha-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N-6-methyladenosine (m(6)A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m(6)A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3 beta) and inhibited its kinase activity, thus releasing beta-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression. Conclusions: Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/beta-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment.

Automated summary

This study identified a hypoxia-induced lncRNA called STEAP3-AS1, which was highly expressed in CRC tissues and correlated with poor prognosis. STEAP3-AS1 interacted with YTHDF2 to protect STEAP3 mRNA from degradation, leading to increased expression of STEAP3 protein and promoting CRC proliferation and metastasis.