A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability

Abstract

The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed genome-wide transcriptome analyses in an isogenic, triple negative breast cancer (TNBC/basal-like) progression cell lines using a 3D cell culture model. We identified significantly altered expression of 1853 lncRNAs, including ~500 natural antisense transcript (NATs) lncRNAs. A significant number of breast cancer-deregulated NATs displayed co-regulated expression with oncogenic and tumor suppressor protein-coding genes in cis. Further studies on one such NAT, PDCD4-AS1 lncRNA reveal that it positively regulates the expression and activity of the tumor suppressor PDCD4 in mammary epithelial cells. Both PDCD4-AS1 and PDCD4 show reduced expression in TNBC cell lines and in patients, and depletion of PDCD4-AS1 compromised the cellular levels and activity of PDCD4. Further, tumorigenic properties of PDCD4-AS1-depleted TNBC cells were rescued by exogenous expression of PDCD4, implying that PDCD4-AS1 acts upstream of PDCD4. Mechanistically, PDCD4-AS1 stabilizes PDCD4 RNA by forming RNA duplex and controls the interaction between PDCD4 RNA and RNA decay promoting factors such as HuR. Our studies demonstrate crucial roles played by NAT lncRNAs in regulating post-transcriptional gene expression of key oncogenic or tumor suppressor genes, thereby contributing to TNBC progression.

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“…Functionally, dysregulation of lncRNAs is closely associated with aberrant biological behaviors of human cancers [28]. It is noteworthy some lncRNAs oriented in antisense direction with respect to a protein coding loci in the opposite strand usually act as regulators in many pathological processes [29]. Previous studies have shown that the natural antisense transcripts play critical roles in various physiological and pathological processes through regulating gene promoter activation and transcription [30][31][32].…”

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“…SHAP value in gene expression showed that RBM20 gene expression contributed more in luminal B subtype than other subtypes (Figure 5D). The finding is accordant with the public results which proves that RBM20 gene expression is correlated with PDCD4-AS1/PDCD4, a tumor suppressor in TNBC cell lines 29 and a subset of TNBC potentially benefit therapy targeting luminal subtype’s typical pathways 30 . In other examples, the SHAP value of TFAP2B shows it is an important gene feature in breast cancer (Figure 5D).…”

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“…For instance, Sun and colleagues reported that lncRNA HOXA11‐AS promoted gastric cancer tumorigenesis through functioning as scaffold of chromatin modification factors LSD1, PRC2, and DNMT1 . In addition, lncRNA PDCD4‐AS1 contributes to breast cancer progression by stabilizing PDCD4 mRNA through forming RNA duplex and controlling PDCD4 mRNA’s interaction with RNA decay promoting factor HuR . Moreover, LINC01234 promotes the malignancy of gastric cancer via acting as a competing endogenous RNA for miR‐204‐5p to regulate CBFB expression …”