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Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.

ABSTRACT: Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes metastasis and is predictive of decreased survival. Here, we describe a long-range transcriptional enhancer of the HOTAIR gene that binds several hormone receptors and associated transcription factors, interacts with the HOTAIR promoter and augments transcription. This enhancer is dependent on Forkhead-Box transcription factors and functionally interacts with a novel alternate HOTAIR promoter. HOTAIR expression is negatively regulated by oestrogen, positively regulated by FOXA1 and FOXM1, and is inversely correlated with oestrogen receptor and directly correlated with FOXM1 in breast tumours. The combination of HOTAIR and FOXM1 enables greater discrimination of endocrine therapy responders and non-responders in patients with oestrogen receptor positive breast cancer. Consistent with this, HOTAIR expression is increased in cell-line models of endocrine resistance. Analysis of breast cancer gene expression data indicates that HOTAIR is co-expressed with FOXA1 and FOXM1 in HER2-enriched tumours, and these factors enhance the prognostic power of HOTAIR in aggressive HER2+?breast tumours. Our study elucidates the transcriptional regulation of HOTAIR, identifies HOTAIR and its regulators as novel biomarkers of patient response to endocrine therapy and corroborates the importance of transcriptional enhancers in cancer.

SUBMITTER: Milevskiy MJ

PROVIDER: S-EPMC5179926 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.

Milevskiy Michael J G MJ Al-Ejeh Fares F Saunus Jodi M JM Northwood Korinne S KS Bailey Peter J PJ Betts Joshua A JA McCart Reed Amy E AE Nephew Kenneth P KP Stone Andrew A Gee Julia M W JM Dowhan Dennis H DH Dray Eloise E Shewan Annette M AM French Juliet D JD Edwards Stacey L SL Clark Susan J SJ Lakhani Sunil R SR Brown Melissa A MA

Human molecular genetics 20160704 15

Predicting response to endocrine therapy and survival in oestrogen receptor positive breast cancer is a significant clinical challenge and novel prognostic biomarkers are needed. Long-range regulators of gene expression are emerging as promising biomarkers and therapeutic targets for human diseases, so we have explored the potential of distal enhancer elements of non-coding RNAs in the prognostication of breast cancer survival. HOTAIR is a long non-coding RNA that is overexpressed, promotes meta ...[more]

PMID: 27378691

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Project description:BackgroundBreast cancer (BRCA) is the leading cause of cancer-related death in women worldwide. Pre- and postoperative radiotherapy play a pivotal role in BRCA treatment but its efficacy remains limited and plagued by the emergence of radiation resistance, which aggravates patient prognosis. The long noncoding RNA (lncRNA)-implicated mechanisms underlying radiation resistance are rarely reported. The aim of this study was to determine whether lncRNA HOX transcript antisense RNA (HOTAIR) modulated the radiosensitivity of breast cancer through HSPA1A.MethodsA Gammacell 40 Exactor was used for irradiation treatment. Bioinformatic tools and luciferase reporter assay were adopted to explore gene expression profile and demonstrate the interactions between lncRNA, miRNA and target mRNA 3'-untranslated region (3'-UTR). The expression levels of certain genes were determined by real-time PCR and western-blot analyses. in vitro and in vivo functional assays were conducted by cell viability and tumorigenicity assays.ResultsThe levels of oncogenic lncRNA HOTAIR were positively correlated with the malignancy of BRCA but reversely correlated with the radiosensitivity of breast cancer cells. Moreover, the expression levels of HOTAIR were positively associated with those of heat shock protein family A (Hsp70) member 1A (HSPA1A) in clinical BRCA tissues and HOTAIR upregulated HSPA1A at the mRNA and protein levels in irradiated BRCA cells. Mechanistically, miR-449b-5p restrained HSPA1A expression through targeting the 3'-UTR of HSPA1A mRNA, whereas HOTAIR acted as a competing sponge to sequester miR-449b-5p and thereby relieved the miR-449b-5p-mediated HSPA1A repression. Functionally, HOTAIR conferred decreased radiosensitivity on BRCA cells, while miR-449b-5p overexpression or HSPA1A knockdown abrogated the HOTAIR-enhanced BRCA growth under the irradiation exposure both in vitro and in vivo.ConclusionsLncRNA HOTAIR facilitates the expression of HSPA1A by sequestering miR-449b-5p post-transcriptionally and thereby endows BRCA with radiation resistance.Key pointsTherapeutically, HOTAIR and HSPA1A may be employed as potential targets for BRCA radiotherapy. Our findings shed new light into the mechanism by which lncRNAs modulate the radiosensitivity of tumors.

Dataset Information

Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.

Publications

Long-range regulators of the lncRNA HOTAIR enhance its prognostic potential in breast cancer.

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