Long Noncoding RNA HOTAIR Regulates Polycomb-Dependent Chromatin Modification and Is Associated with Poor Prognosis in Colorectal Cancers

Abstract

The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression. Cancer Res; 71(20); 6320-6. Ó2011 AACR.

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…In the case of CRC, the administration of specific siRNAs targeting the oncogenic HOTAIR, CCAT2, and uc.73a transcripts was shown to decrease the invasion or proliferation of colon cancer cells. 20,58,62 Although the results presented in these studies are only preliminary in vitro data, these reports suggest that RNAi-based therapy strategies are amenable to further development, particularly for cellular therapies.…”

“…One such lncRNA, HOTAIR, was highly expressed in cancerous tissues compared with the corresponding noncancerous tissues in stage IV CRC patients, and the levels of HOTAIR were correlated with liver metastasis. 20 HULC is an lncRNA that was identified in human HCC tissues; intriguingly, HULC expression was found to be high in CRC liver metastatic nodules but not in primary CRC tissues or the corresponding normal tissues. 89 These results suggest that individual lncRNAs or lncRNA panels could potentially be utilized as tailored biomarkers for monitoring CRC metastasis.…”

“…17,24 For example, the antisense intergenic RNA HOX Antisense Intergenic RNA (HOTAIR) is highly expressed in multiple types of primary somatic tumors, such as hepatocellular carcinoma, 25,26 pancreatic cancer, 27 and gastric cancer, 28 as well as some metastatic tumors, including metastatic breast tumors 29 and melanoma. 30 Moreover, high HOTAIR level is associated with poor patient survival rate 20,27 and tumor recurrence. 25 It was discovered that HOTAIR represses transcription across 40 kb of the HOXD locus by acting as a scaffold of histone modification complexes; it binds with polycomb chromatin remodeling complexes in trans, which lead to alterations of cells' epigenetic state and subsequent gene expression.…”

The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine

“…For example, increased expression of lncRNA HOTAIR was shown to be associated with metastasis in breast cancer patients, having a unique association with patient prognosis. 24 In addition, HOTAIR expression levels was found to correlate with metastasis in colorectal cancer, 85 and to predict tumor recurrence in HCC patients who have undergone liver transplant therapy. 86 Ideally, biomarkers should be easily accessible such that they can be sampled non-invasively.…”

Rôle des longs ARN non codants dans le développement normal et pathologique

“…Parmi les exemples de lncRNA associés au cancer, le rôle de HOTAIR a été le plus étudié. Plusieurs publications ont rapporté une surexpression de HOTAIR dans différents cancers, où il participerait parfois à la formation de métastases [25,26]. MALAT1 (metastasis associated lung adenocarcinoma transcript 1) est un autre lncRNA très étudié ; sa surexpression est associée à l'état métastatique de tumeurs.…”