PUBLICATION
Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA
- Authors
- Zhou, L., Jiang, J., Huang, Z., Jin, P., Peng, L., Luo, M., Zhang, Z., Chen, Y., Xie, N., Gao, W., Nice, E.C., Li, J.Q., Chen, H.N., Huang, C.
- ID
- ZDB-PUB-220824-6
- Date
- 2022
- Source
- Molecular Cancer 21: 168 (Journal)
- Registered Authors
- Keywords
- Colorectal cancer, Hypoxia, LncRNA STEAPS-AS1, STEAP3, Wnt/β-catenin, YTHDF2, m6A modification
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Colorectal Neoplasms*/pathology
- Gene Expression Regulation, Neoplastic
- Glycogen Synthase Kinase 3 beta/metabolism
- Hypoxia/genetics
- In Situ Hybridization, Fluorescence
- Iron/metabolism
- Mice
- MicroRNAs*
- RNA, Long Noncoding*/metabolism
- RNA, Messenger/genetics
- RNA-Binding Proteins
- Transcription Factors/genetics
- Wnt Signaling Pathway/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins
- beta Catenin/genetics
- beta Catenin/metabolism
- PubMed
- 35986274 Full text @ Mol. Cancer
Citation
Zhou, L., Jiang, J., Huang, Z., Jin, P., Peng, L., Luo, M., Zhang, Z., Chen, Y., Xie, N., Gao, W., Nice, E.C., Li, J.Q., Chen, H.N., Huang, C. (2022) Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA. Molecular Cancer. 21:168.
Abstract
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-1α. 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/β-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-1α-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 N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-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 (GSK3β) and inhibited its kinase activity, thus releasing β-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/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping