A new hypoxia-responsive lncRNA in metastatic breast cancer

Abstract

© Non-coding RNA Investigation. All rights reserved. Non-coding RNA Investig 2020;4:5 | http://dx.doi.org/10.21037/ncri.2020.03.03 Metastatic breast cancer, refers to the spread of the disease from the breast to other parts of the body, most often to bone, brain, liver or lungs. Despite advances in breast cancer management, most cancer deaths result from metastases that are resistant to systemic therapies (1). Hypoxia (or reduced oxygen availability) is a hallmark of the breast tumor microenvironment and plays an important role in metastatic progression. Breast tumor cells adapt to hypoxia by increasing the activity of the hypoxiainducible transcription factors (HIF1 and HIF2), which regulate the expression of target genes involved in cancer progression (2). Recent studies have implicated long noncoding RNAs (lncRNAs) in hypoxia/HIF-associated breast cancer metastasis, through various mechanisms. Notable examples include the nuclear lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), which is widely reported as a metastasis-promoting lncRNA, however a recent study provided strong evidence that MALAT1 suppresses breast cancer metastasis through inactivation of the TEAD transcription factor (3). HOTAIR (HOX transcript antisense RNA) is highly expressed in primary breast tumors and metastases and associated with poor prognosis. HOTAIR promotes epithelial to mesenchymal transition (EMT) by recruiting the polycomb repressive complex-2 (PRC2) to epigenetically silence target gene promoters (4). Furthermore, hypoxic induction of NEAT1 (nuclear paraspeckle assembly transcript 1) induces the formation of nuclear structures called paraspeckles and retention of F11R (also known as junctional adhesion molecule 1) mRNA in the nucleus (5). Induction of NEAT1 in hypoxia also leads to hallmarks of increased tumorigenesis including acceleration of tumor cell proliferation and inhibition of apoptosis (5). The recent study by Niu et al. (6), provides another example of a hypoxia-responsive lncRNA involved in metastatic breast cancer. The authors initially used RNAseq to identify an hypoxia-inducible antisense lncRNA, called RAB11B-AS1 from MDA-MB-231 breast cancer cells under hypoxic conditions (7). Subsequent ChIP-seq and qPCR showed that HIF2, but not HIF1, was enriched at the RAB11B-AS1 promoter and responsible for hypoxiainduced lncRNA expression. Nui and colleagues then investigated the oncogenic role of RAB11B-AS1 in vitro and in vivo through gainand loss-of function studies. They found ectopic expression of RAB11B-AS1 promoted cell migration and invasion in MDA-MB-231 and SUM159 breast cancer cells, whereas RAB11B-AS1 depletion caused the opposite effect. Orthotopic injection of MDAMB-231 cells, ectopically expressing RAB11B-AS1, into the mammary fat pads of NSG mice, did not affect primary tumor growth, but showed increased expression of the endomucin capillary marker and extensive metastases to the lungs and liver as compared to the control group. Collectively, these results suggest that hypoxia-induced RAB11B-AS1 promotes metastasis of breast cancer cells to distant tissues. To investigate the mechanisms by which RAB11B-AS1 contributes to angiogenesis, the authors analysed RNAseq data from RAB11B-AS1-overexpressed MDA-MB-231 under hypoxia. Gene ontology analysis indicated multiple biological process likely contribute to the phenotype, although it was difficult to rank the results as no value for Editorial Commentary