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. 2016 May 1;49(3):255–260. doi: 10.1111/cpr.12252

CCAT1: a pivotal oncogenic long non‐coding RNA in human cancers

Yu Xin 1, Zheng Li 2, Jianxiong Shen 2,✉, Matthew T V Chan 3, William Ka Kei Wu 3,4
PMCID: PMC6496795  PMID: 27134049

Abstract

Long non‐coding RNAs (lncRNAs) compose a group of non‐protein‐coding RNAs ‐ more than 200 nucleotides in length. Recent studies have shown that lncRNAs play important roles in different cellular processes, including proliferation, differentiation, migration and invasion. Deregulation of lncRNAs has been widely reported in human tumours, in which they are able to function as either oncogenes (on the one hand) or tumour suppressor genes (on the other). Deregulation of CCAT1 (colon cancer–associated transcript‐1), an oncogenic lncRNA, has been documented in different types of malignancy, such as gastric cancer, colorectal cancer and hepatocellular carcinoma. In this regard, enforced expression of CCAT1 exerts potent tumorigenic effects by promoting cell proliferation, invasion and migration. Recent evidence has also shown that CCAT1 may serve as a prognostic cancer biomarker. In this review, we provide an overview of current evidence relating to the role and biological function of CCAT1 in tumour development.

Introduction

Long non‐coding RNAs (lncRNAs) consist of a group of non‐coding RNAs with more than 200 nucleotides in length 1, 2, 3, 4. These RNAs demonstrate limited protein‐coding potential but could regulate gene expression transcriptionally and post‐transcriptionally 5, 6, 7. Deregulation of lncRNAs has been observed in a variety of human diseases, including cancer 8, 9, 10. The functional involvement of lncRNAs in tumorigenesis has received much attention over the past decade 11, 12, 13. Pertinent to clinical practice, deregulation of lncRNAs in many cancer types has been associated with clinicopathological parameters, including metastasis, patients' survival and recurrence 6, 14, 15. lncRNA deregulation also contributes to cancer progression through abnormal regulation of genes involved in cancer‐related cellular processes, including cell proliferation and invasion 12, 16, 17, 18, 19, 20, 21, 22, 23, 24.

Colon cancer–associated transcript‐1 (CCAT1) is a newly discovered lncRNA with 2628 base pairs in length 25, 26, 27. CCAT1 gene is located on chromosome 8q24.21 and in the vicinity of c‐MYC, a well‐known transcription factor 25, 28. CCAT1 was first found to be upregulated in colon cancer 29. Recently, CCAT1 was found to be consistently deregulated in various cancer types 27, 30, 31. The location of CCAT1 gene on chromosome 8q24.21 is crucial as this area is a ‘hot spot’ harbouring multiple genetic alternations in both colon and prostate cancers 32.

CCAT1 is an enhancer‐derived RNAs transcribed from a distal enhancer 515 kb upstream of the c‐MYC gene (Fig. 1) 33, 34. CCAT1 contains two exons and a poly‐A tail and is mainly expressed in the nucleus. In colon cancer cells, CCAT1 is localized at its site of transcription 26, 29, which is important for mediating the long‐range chromatin interactions between CCAT1 gene and c‐MYC in conjunction with an enhancer 335 kb upstream of c‐MYC. In this manner, CCAT1 transcriptionally activates c‐MYC in a cis‐acting manner. Depletion of CCAT‐1 could, therefore, reduce the transcription of c‐MYC gene.

Figure 1.

Figure 1

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CCAT 1 is an enhancer‐derived RNA s transcribed from a distal enhancer 515 kb upstream of the c‐ MYC gene.

In this review, we discuss the roles of CCAT1 as one of the most important regulatory RNAs in human cancer in relation to its deregulation, molecular functions and clinical significance (Table 1).

Table 1.

Functional characterization of the CCAT1 in tumours

Cancer types Expression Phenotypes affected Related gene Role References
Colorectal cancer Upregulated Proliferation, invasion c‐Myc Oncogenic 26, 27, 29, 43, 44, 45
Gastric cancer Upregulated Proliferation, invasion c‐Myc, ERK/MAPK Oncogenic 25, 52, 53
Hepatocellular carcinoma Upregulated Proliferation, migration let‐7, HMGA2, c‐Myc Oncogenic 28, 30, 65
Gallbladder cancer Upregulated Proliferation, invasion Bmi1, miR‐218‐5p Oncogenic 69
Ovarian cancer Upregulated Metastasis Oncogenic 77
Breast cancer Upregulated Oncogenic 31
Lung cancer Upregulated Proliferation Oncogenic 78, 80
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Colorectal cancer

Colorectal cancer is a common malignancy with around 1.2 million newly diagnosed cases worldwide each year 35, 36, 37. Its mortality rate is the third highest among all cancers, leading to approximately 0.6 million deaths annually 36, 38, 39. Currently, CEA and CA19‐9 are the two most frequently used clinical diagnostic biomarkers 40, 41, 42. However, they have little significance in early diagnosis of colorectal cancer because of their lack of sensitivity and specificity. Identification, validation and clinical application of novel colorectal cancer‐specific biomarkers may, therefore, improve the diagnostic accuracy, staging, patient follow‐up and treatment selection of this prevalent disease.

Nissan et al. demonstrated that the expression level of CCAT1 was significantly upregulated in colon adenocarcinoma as compared with healthy controls 29. The expression of CCAT1 was significantly increased in both the early and late stages of colon cancer. CCAT1 was also strongly expressed in adenomatous polyps, tumour‐proximal colonic epithelium, liver metastasis and the associated lymph nodes. Pertinent to non‐invasive diagnosis, CCAT1 overexpression was detectable in 40% of peripheral blood samples of colorectal cancer patients, while it was largely undetectable in healthy controls. Alaiyan et al. also identified significant upregulation of CCAT1 in both pre‐malignant and malignant lesions of the colon, including adenomatous polyps, primary tumour tissue, normal mucosa adjacent to primary tumour and lymph node, liver and peritoneal metastases 27.

In relation to prognostication, Ye et al. showed that the expression level of CCAT1 was significantly correlated with tumour staging, local infiltration depth, vascular invasion and CA19‐9 level 43. CCAT1 also predicted the sensitivity of colon cancer cells to bromodomain and extraterminal (BET) inhibition, which preferentially reduced the growth of colon cancer with the CpG island methylator phenotype. In this regard, CCAT1 was sensitive to BET inhibition, correlated with c‐MYC transcript and cell growth, and proposed to be a biomarker for selecting patients who are most likely to benefit from BET inhibitors 44. Another study investigated the diagnostic ability of a CCAT1‐specific peptide nucleic acid‐based molecular beacon (CCAT1 TO‐PNA‐MB) for detection of colorectal cancer 26. The data showed that CCAT1 TO‐PNA‐MB could serve as a diagnostic tool for colorectal cancer in vitro, ex vivo and in situ (human colon biopsies). Hybridization of TO‐PNA‐MB could detect CCAT1 expression in all (4/4) human colon biopsies with pre‐cancerous adenomas, as well as in all (8/8) patients with invasive adenocarcinoma (penetrating the bowel wall). He et al. 45 further demonstrated that c‐Myc could reciprocally increase CCAT1 expression through binding to its promoter region while overexpression of CCAT1 promoted colon cancer cell proliferation and invasion. To conclude, CCAT1 is a highly specific and readily detectable diagnostic biomarker for colorectal cancer, in which its upregulation contributes to both tumour growth and metastasis.

Gastric cancer

Gastric cancer is the fourth most frequent cancer and the second leading cause of cancer‐related death worldwide 46, 47, 48, 49. Although Helicobacter pylori and Epstein–Barr virus are two major aetiological factors of gastric cancer, our understanding of its molecular mechanisms remains largely incomplete 50, 51, 52. It is, therefore, crucial to identify novel molecular abnormalities in this deadly disease.

CCAT1 was upregulated in gastric carcinoma tissues compared with normal tissues 53, 54. Similar to colorectal cancer, the transcription factor c‐Myc increased the expression of CCAT1 by directly binding to its promoter region 25. The expression level of CCAT1 was correlated with cancer growth, lymph node metastasis and distal metastatic disease in gastric cancer. Moreover, CCAT1 promoted gastric cancer cell proliferation and migration in vitro. Mizrahi et al. also demonstrated that the expression level of CCAT1 was significantly higher in gastric cancer samples than that in the control group. In addition, CCAT1 expression was elevated in human gastric carcinoma cell lines. The expression levels of CCAT1 were found to be highest in tissues from recurrent gastric cancer cases 53. In conclusion, expression of CCAT1 is increased in gastric cancer, in which it serves as a potential marker for metastatic disease. Functionally, CCAT1 acts as an oncogene in gastric cancer, suggesting its potential utilization as a therapeutic target.

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most frequent solid tumour and the third leading cause of cancer deaths worldwide 55, 56, 57, 58. Chronic infection with either hepatitis B or C virus plays significant roles in the development of HCC 59, 60, 61. Despite recent advances in surgery and medical treatment, the prognosis of HCC patients remains extremely poor 62, 63, 64. Therefore, it is crucial to understand the pathogenesis of HCC.

The expression level of CCAT1 was significantly elevated in HCC tissues compared with matched non‐cancerous hepatic tissues 28, 30, 65. In addition, the expression level of CCAT1 predicted poor prognosis in HCC, correlated with tumour size, microvascular invasion and alpha foetal protein (AFP) expression. Furthermore, CCAT1 promoted the proliferation and migration of HCC cells in vitro through binding and antagonizing let‐7, a tumour‐suppressive microRNA, and thereby derepressing the expression of let‐7 targets HMGA2 and c‐Myc. Taken together, CCAT1 is involved in the development and progression of HCC via functioning as a let‐7 sponge. CCAT1 might act as an oncogene in HCC, suggesting its potential utilities as a prognostic marker and a therapeutic target.

Gallbladder cancer

Gallbladder cancer is fifth most frequent gastrointestinal malignancy 66, 67, 68, 69. The pathogenesis of gallbladder carcinoma remains largely unknown. Therefore, it is of great importance to study its molecular mechanisms.

The expression of CCAT1 was higher in gallbladder cancer tissues compared with adjacent normal tissues 70. In addition, CCAT1 overexpression increased the expression of Bmi1, which is the target gene of miRNA‐218‐5p. Further analysis showed that CCAT1 knockdown inhibited the proliferation and invasiveness of gallbladder cancer cells, at least in part, through regulation of Bmi1. In this regard, transcript level of CCAT1 was correlated with Bmi1 in gallbladder cancer tissues. In conclusion, CCAT1 functions as an oncogenic lncRNA in gallbladder cancer in part through sponging miRNA‐218‐5p.

Ovarian cancer

Ovarian cancer is the most lethal gynaecological cancer and the fifth leading cause of cancer‐related death 71, 72, 73, 74. There has been no improvement in its mortality rate over the last 20 years 75, 76, 77. Much attention has, therefore, been given to the pathogenic mechanisms, particularly pathways that regulate metastasis of ovarian cancer.

Compared with the parental SKOV3 cells, the invasive ability of the SKOV3.ip1 cell line was significantly higher 78. Among 4956 detected lncRNAs in SKOV3.ip1 cells, the expression levels of 583 lncRNAs were upregulated and the expression levels of 578 were downregulated as compared with SKOV3 cells by microarray. Moreover, reverse transcription‐quantitative PCR confirmed the deregulation of seven analysed lncRNAs (MALAT1, H19, UCA1, CCAT1, LOC645249, LOC100128881 and LOC100292680). These findings implicated that CCAT1 might play a role in ovarian cancer metastasis. Further studies are needed to determine the exact role of CCAT1 in ovarian cancer.

Breast cancer

Zhang et al. 31 demonstrated that the expression of CCAT1 was upregulated in breast cancer tissues compared with the adjacent normal tissues. The high expression of CCAT1 was correlated with tumour–node–metastasis (TNM) staging, differentiation grade and lymph node metastases. Patients with high CCAT1 expression had a poor overall and progression‐free survival. These results suggested that CCAT1 might function as an oncogenic lncRNA and serve as a potential prognostic marker in breast cancer.

Lung cancer

White et al. 79 depicted the landscape of lncRNA deregulation in lung cancer by integrative analysis of publicly available transcriptome sequencing data from 567 lung adenocarcinoma and squamous cell carcinoma tumours. By comparison with matched control, the authors identified 111 differentially expressed lncRNAs, including CCAT1. In a subsequent study, the same group demonstrated that knockdown of CCAT1 could potently inhibit lung cancer cell proliferation 80.

Conclusion

CCAT1 is a relatively well‐characterized oncogenic lncRNA, which is upregulated in many types of cancer, including colorectal cancer, gastric cancer, HCC, gallbladder cancer, ovarian cancer, breast cancer and lung cancer. Functional characterization has also demonstrated that CCAT1 could promote tumour cell proliferation, migration and invasion. Although the involvement of c‐Myc in the oncogenic function of CCAT1 has been demonstrated, its detailed upstream and downstream molecular mechanisms remain to be systematically studied. Pertinent to clinical utility, the overexpression of CCAT1 is very often associated with poor clinical outcomes. Therefore, this lncRNA may serve a prognostic biomarker. With more efforts being put forth to the study of lncRNAs especially CCAT1, it is hopeful that CCAT1 will obtain routine clinical utility at last.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (grant number 81401847).

Xin Yu and Zheng Li contributed equally to this work.

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