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

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.

Long Non-Coding RNA HOXA-AS2 Regulates Malignant Glioma Behaviors and Vasculogenic Mimicry Formation via the MiR-373/EGFR Axis

“…Xie et al [23] showed that HOXA-AS2 epigenetically silences P21, PLK3, and DDIT3 in gastric cancer cells via binding to EZH2. Moreover, Ding et al [13] proved that HOXA-AS2 recruits EZH2 and LSD1 to the p21 and KLF12 promoter regions, which inhibits p21 and KLF12 translation. Accordingly, further investigations of whether other mechanisms are involved in HOXA-AS2-mediated miR-373 expression changes should be performed.…”

“…The lncRNA HOXA cluster antisense RNA 2 (HOXA-AS2) was first reported to be an apoptosis suppressor in NB4 promyelocytic leukemia cells treated with all-trans retinoic acid [12]. Subsequent studies showed that HOXA-AS2 is aberrantly expressed in several human cancers and functions as an oncogene [13, 14]. However, little is known concerning its expression in glioma and its potential role in glioma malignancy and VM.…”

The Biological Effect and Clinical Application of Long Noncoding RNAs in Colorectal Cancer

“…The results of clinical features showed that TUSC7 was associated with tumor size, HOTAIR with tumor size and TNM-stage. In table 1, we concluded a correlation with CRC clinical features and lncRNAs for visually understanding that lncRNAs might be as markers for CRC diagnosis (Table 1) [16, 17, 47, 57, 75-80]. Sun et al reported that ANRIL could enhance cell mobility and invasion by in-vitro tube formation HLECs invasion.…”

“…The results of clinical features showed that H19 was associated with TNM-stage, tumour differentiation, HOTAIR with TNM-stage, tumour differentiation vessel invasion. Similarly, the FOXP4-AS1and HOXA-AS2 showed onco-role in promoting CRC proliferation and apoptosis [16, 17]. These evidences displayed unfavourable prognostic markers for CRC patients.…”

“…Increasing reports suggested that lncRNAs, as a tumor regulator, were participated in complex network of biological regulation [12, 13]. Increasing lncRNAs were reported as the markers in CRC diagnosis, such as MALAT1, HOTAIR, H19 and CCAT [14-17]. Long non-coding RNA RP11-708H21.4 was identified to be down-regulated in CRC.…”