Abstract
Colon cancer-associated transcript 2 (CCAT2) is an intensively studied lncRNA with important regulatory roles in cancer. As such, cumulative studies indicate that CCAT2 displays a high functional versatility due to its direct interaction with multiple RNA binding proteins, transcription factors, and other species of non-coding RNA, especially microRNA. The definitory mechanisms of CCAT2 are its role as a regulator of the TCF7L2 transcription factor, enhancer of MYC expression, and activator of the WNT/β-catenin pathway, as well as a role in promoting and maintaining chromosome instability through the BOP1–AURKB pathway. Additionally, we highlight how the encompassing rs6983267 SNP has been shown to confer CCAT2 with allele-specific functional and structural particularities, such as the allelic-specific reprogramming of glutamine metabolism. Additionally, we emphasize CCAT2’s role as a competitive endogenous RNA (ceRNA) for multiple tumor suppressor miRNAs, such as miR-4496, miR-493, miR-424, miR-216b, miR-23b, miR-34a, miR-145, miR-200b, and miR-143 and the pro-tumorigenic role of the altered regulatory axis. Additionally, due to its upregulation in tumor tissues, wide distribution across cancer types, and presence in serum samples, we outline CCAT2’s potential as a biomarker and disease indicator and its implications for the development of resistance against current cancer therapy regiments and metastasis.
Highlights
Smaller species of ncRNA are mainly represented by microRNA, which are considered to range between 19 and 25 nucleotides and are mainly involved in regulating gene expression post-transcriptionally, targeting specific mRNAs based on the presence of complementary seed sequences [2–5]
cancer-associated transcript 2 (CCAT2) interacts with the RNA binding protein (RBP) ELAVL1/HuR at the nuclear level, a key factor involved in mRNA stabilization, previously shown to promote proliferation, apoptosis, and differentiation in multiple types of cancer [108]
Shi et al showed that ELAVL1 knockdown decreased Agt5 expression, this effect being restored through CCAT2 upregulation. These findings indicate that CCAT2 promotes the proliferative processes by targeting miR-4496 and the activation of autophagy via, and interacting with ELAVL1, and downregulating Agt5. [69]
Summary
While the existence of non-coding species of RNA has been acknowledged for several decades already, the advent of modern sequencing techniques has allowed their detailed characterization and classification. The lncRNA HOTAIR, initially highlighted as a trans epigenetic regulator [12] of the key developmental HOX genes through its direct in different developmental [8,9] and pathological processes [10,11], which indicated their high functional variability. MYC is one of the downstream targets of the Wnt/β-catenin pathway, highlighting the dual potentiating role of CCAT2 in this tumor-promoting feedback loop. High WISP1 levels stimulate the expression of its effectors VEGF-A, MMP2, and ICAM-1, with important roles in angiogenesis, epithelial-to-mesenchymal transition (EMT) and metastasis [26] This interplay between CCAT2, MYC, and WNT molecules has been explored and confirmed in multiple cancers in recent years and is responsible for the main pro-tumorigenic roles of CCAT2. Similar studies confirmed the presence of the mechanism in the case of thyroid [27], ovarian [28], clear cell renal cell carcinoma [29], and breast cancers [30]
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