ZFAS1: A novel vital oncogenic lncRNA in multiple human cancers

Abstract Long noncoding RNAs (lncRNAs) are a class of noncoding, endogenous, single‐stranded RNAs longer than 200 nucleotides in length that are transcribed by RNA polymerase II. Mounting evidence has indicated that lncRNAs play key roles in several physiological and pathological processes by modifying gene expression at the transcriptional, posttranscriptional, epigenetic, and translation levels. Many reports have demonstrated that lncRNAs function as potential oncogene or tumour suppressors and thus play vital regulatory roles in tumourigenesis and tumour progression. ZNFX1 antisense RNA 1 (ZFAS1), a novel lncRNA transcribed in the antisense orientation of zinc finger NFX1‐type containing 1(ZNFX1), was found to be increased in multiple cancers, such as gastric cancer and hepatocellular carcinoma, contributing to cancer development and progression. In the present review, we summarized recent progression on study of the functions and underlying molecular mechanisms of ZFAS1 related to occurrence and development of multiple cancers.

ZNFX1 antisense RNA 1 (ZFAS1), a novel lncRNA transcribed from the antisense orientation of zinc finger NFX1-type containing 1(ZNFX1), is located on chromosome 20q13.13 ( Figure 1). 12 Recent research has reported that ZFAS1 may act an emerging regulatory factor in multiple diseases, such as acute myocardial infarction, 13,14 rheumatoid arthritis, 15 and cancer. 16 Accumulating evidence has suggested that the abnormal expression of ZFAS1 contributes to the occurrence and development of various cancers, including gastric cancer, hepatocellular carcinoma, colorectal cancer, glioma, osteosarcoma, ovarian cancer, acute myeloid leukaemia, nonsmall cell lung cancer (NSCLC), oesophageal squamous cell carcinoma, and breast cancer. In this review, we summarized recent progression regarding study of the functions and underlying mechanisms of ZFAS1 in the occurrence and development of various cancers.

| D ISCOVERY OF ZFA S1
ZFAS1, firstly studied in breast cancer by Marjan, is transcribed from the gene ZNFX1 on the antisense DNA strand near the 5′ ZFAS1 hosts three small nucleolar RNAs (snoRNAs), including Snord12, Snord12b, and Snord12c. 12 SnoRNAs, a class of RNA molecules with 60-150 nt in length which may be involved in the chemical modifications of other RNAs, like transfer RNAs, ribosomal RNAs, and small nuclear RNAs. 17 Current research has indicated that upregulation of ZFAS1 is positively correlated with clinicopathological features and prognosis, including TNM stage, lymph-node metastasis, F I G U R E 1 ZFAS1 was located on chromosome 20q13. 13 and transcribed in antisense orientation of ZNFX1 and also hosts three small nucleolar RNAs, including Snord12, Snord12b, and Snord12c The functions and underlying molecular mechanisms of ZFAS1 in various cancers are summarized in Table 2 and detailed in the rest of this review.

| Gastric cancer
Current research trends have explored the function and molecular mechanisms of ZFAS1in gastric cancer. Zhou et al, 25 Pan et al, 26

| Hepatocellular carcinoma
Li et al 28

| Osteosarcoma
In osteosarcoma tissues and cell lines, Liu et al and Li et al 32,33 showed that ZFAS1 was markedly upregulated.

| Acute myeloid leukaemia
When compared with normal cell lines, Guo et al 30

| Nonsmall cell lung cancer
Tian et al 36

| Breast cancer
Marjan et al 12

| Transcriptional regulation
Further research has demonstrated that ZFAS1 could simultaneously interact with EZH2 and LSD1/CoREST to inhibit KLF2 and NKD2 transcription. Rescue experiments revealed that ZFAS1 was partly relied on suppressing KLF2 and NKD2 expression to exert its oncogenic effects ( Figure 2G). SP1 was also demonstrated to be an upstream factor for the activation of ZFAS1 expression ( Figure 2H). Moreover, Hansji et al showed that ZFAS1 was induced upon ribosome biogenesis, revealing a role in synthesis or assembly of ribosomes.

| EMT signalling pathway
EMT plays an essential role in both physiological and pathological processes, such as embryonic development as well as the occurrence and development of tumours. 40 Notch signalling pathway ( Figure 2E).

| p53 signalling pathway
The p53 protein, a nuclear transcription factor, modified the expression of multiple genes which are involved in a variety of biological processes, including the cell cycle, apoptosis, and DNA repair. 46 Thorenoor et al demonstrated that decreased ZFAS1 contributed to cell-cycle arrest and induction of apoptosis by reducing the expression of p53 and cyclin B1 and promoting PARP cleavage ( Figure 2F).
This finding suggests that ZFAS1 activated the p53 signalling pathway to act oncogenic roles in various cancers.

| CON CLUS I ON AND FUTURE PER S PEC TIVE S
With the rapid development of next-generation sequencing technology, a large amount of evidence has identified dysregulated lncRNAs as potential oncogenes or tumour suppressor genes that play crucial regulatory roles in tumourigenesis and tumour progression. 47  Therefore, the clinical value of ZFAS1 in the diagnosis and treatment of cancers requires more attention.
In summary, ZFAS1 has been shown to have oncogenic function in tumourigenesis and tumour progression and may act as a potential cancer-specific molecular biomarker in the general diagnosis, prognosis, and treatment of cancer. Until this point, research on the mechanism of ZFAS1 has made some progression, but remains in the early stages. Future works will need to emphasize exploration of the precise molecular regulatory mechanisms of ZFAS1 in carcinogenesis and cancer progression, to facilitate the clinical application of ZFAS1 as early as possible.

AUTH O R S' CO NTR I B UTI O N S
AH, SH wrote the manuscript. XL and LZ provided the financial support and reviewed the manuscript. All authors read and approved the final manuscript.

CO N FLI C T O F I NTE R E S T
All authors declare no conflict of interest.