Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer

K Wang,L Wang,Y Lian,Y Zhu,J Wang,J Ding,M Xie,P Peng

doi:10.1038/oncsis.2016.84

Abstract

Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer (CRC) are not known. Here, we identified that HOXA-AS2 is significantly upregulated in CRC tissue. In addition, increased HOXA-AS2 expression is associated with a larger tumor size and an advanced pathological stage in CRC patients. HOXA-AS2 knockdown significantly suppressed proliferation by blocking the G1/S transition and caused apoptosis of CRC cells in vitro and in vivo. The mechanistic investigations showed that HOXA-AS2 could interact with EZH2 (enhancer of zeste homolog 2), LSD1 (lysine specific demethylase 1) and recruit them to p21 (CDKN1A), KLF2 promoter regions to repress their transcription. Furthermore, the rescue experiments demonstrated that HOXA-AS2 oncogenic function is partly through regulating p21. In conclusion, our data suggest that HOXA-AS2 may function as an oncogene by modulating the multiple genes expression involved in CRC proliferation, and also provides a potential target for CRC therapy.

Highlights

Colorectal cancer (CRC) is one of the top three culprits of common malignancies worldwide, with over 1.2 million new cases diagnosed each year.[1,2,3] considerable headway in CRC diagnosis and therapy has been achieved in the past decade, CRC morbidity and mortality remain high, especially in the developed world.[4]
With advances in tiling array and sequencing technologies, it has been revealed that the majority (~97%) of human genome sequences is transcribed into noncoding RNAs
We first found that HOXA-AS2 was significantly upregulated in the CRC tissues compared with the adjacent normal tissues

Summary

Introduction

Colorectal cancer (CRC) is one of the top three culprits of common malignancies worldwide, with over 1.2 million new cases diagnosed each year.[1,2,3] considerable headway in CRC diagnosis and therapy has been achieved in the past decade, CRC morbidity and mortality remain high, especially in the developed world.[4]. Long noncoding RNAs (lncRNAs) are a class of newly discovered noncoding RNA molecules and have attracted the attention of many researchers given their abnormal expression in human diseases.[9,10] Considerable evidence has suggested that lncRNAs are key oncogenes[11,12] or tumor suppressors[13] in human carcinogenesis and are increasingly recognized as future diagnostic, therapeutic or prognostic cancer biomarkers, including for CRC.[14,15,16] Our previous studies demonstrated that downregulation of lncRNA BANCR (BRAF activated noncoding RNA) may contribute to the proliferation of CRC cells, at least in part, through the regulation of p21 protein;[17] lncRNA LOC554202 could induce apoptosis via the caspase cleavage cascades in CRC cells.[18]

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Results

Conclusion