MALAT1 and HOTAIR Long Non-Coding RNAs Play Opposite Role in Prostate Cancer Cells

In the complex network of nuclear hormone receptors, the long non-coding RNAs (lncRNAs) are emerging as critical determinants of hormone action. Here researchers from the Institute of Cell Biology and Neurobiology, Rome investigated the involvement of selected cancer-associated lncRNAs in Estrogen Receptor (ER) signaling. Prior studies by Chromatin Immunoprecipitation (ChIP) Sequencing showed that in prostate cancer cells ERs form a complex with the endothelial nitric oxide synthase (eNOS) and that in turn these complexes associate with chromatin in an estrogen-dependent fashion.

Among these associations (peaks) the researchers focused their attention on those proximal to the regulatory region of HOTAIR and MALAT1. These transcripts appeared regulated by estrogens and able to control ERs function by interacting with ERα/ERβ as indicated by RNA-ChIP. Further studies performed by ChIRP revealed that in unstimulated condition, HOTAIR and MALAT1 were present on pS2, hTERT and HOTAIR promoters at the ERE/eNOS peaks. Interestingly, upon treatment with17β-estradiol HOTAIR recruitment to chromatin increased significantly while that of MALAT1 was reduced, suggesting an opposite regulation and function for these lncRNAs. Similar results were obtained in cells and in an ex vivo prostate organotypic slice cultures.

Schematic representation of the peaks of eNOS by ChIP–Seq, estrogen-dependent LncRNAs expression and eNOS/ERs recruitment in prostate and breast cancer cells


(a,b) Integrated Genome Viewer (IGV 2.3) screenshots showing peaks of eNOS identified by ChIP–Seq at the genomic regions encoding HOTAIR and MALAT1 in two prostate cancer cell lines, LNCaP and C27IM, and in the human endothelial cell line HUVEC, in the absence (NT) or presence of 17β-estradiol (10 nM E2). Region amplified in panel e and f are indicated as red circles. (c,d) Quantification of HOTAIR and MALAT1 expression by qRT-PCR in normal HUVEC, prostate hyperplastic C17IM, BCa (MCF7, MDA-MB 361) and PCa (C27IM, LNCaP, PC3) cells in basal condition (E2 0 h) and after 3 h, 6 h and 24 h of treatment with E2. The results are plotted as fold induction (+/−E2) and represent the average of 5 independent experiments. *p < 0,05 vs E2 0 h. (e,f) Recruitment of Estrogen Receptors (ER) and eNOS, on the promoter region of HOTAIR and MALAT1 by ChIPs in the presence or absence of E2 in HUVEC, breast (MCF7) and prostate (C27IM and LNCaP) cells. The immunoprecipitations were performed using anti ERα (in HUVEC and MCF7), ERβ (in C27IM and LNCaP) and eNOS or no antibody (NoAb) as a negative control. Values are represented as Fold of Induction (+/−E2) and as mean +/−SEM of 4 independent experiments. *p < 0,05 +E2 vs −E2.

Overall, these data provide evidence of a crosstalk between lncRNAs, estrogens and estrogen receptors in prostate cancer with important consequences on gene expression regulation.

Aiello A, Bacci L, Re A, Ripoli C, Pierconti F, Pinto F, Masetti R, Grassi C, Gaetano C, Bassi PF, Pontecorvi A, Nanni S, Farsetti A. (2016) MALAT1 and HOTAIR Long Non-Coding RNAs Play Opposite Role in Estrogen-Mediated Transcriptional Regulation in Prostate Cancer Cells. Sci Rep 6:38414. [article]

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