The lncRNA DRAIC/PCAT29 Locus Constitutes a Tumor-Suppressive Nexus

Long noncoding RNAs (lncRNA) are emerging as major regulators of cellular phenotypes and implicated as oncogenes or tumor suppressors. Here, we report a novel tumor-suppressive locus on human chromosome 15q23 that contains two multiexonic lncRNA genes of 100 kb each: DRAIC (LOC145837) and the recently reported PCAT29. The DRAIC lncRNA was identified from RNA-seq data and is downregulated as prostate cancer cells progress from an androgen-dependent (AD) to a castration-resistant (CR) state. Prostate cancers persisting in patients after androgen deprivation therapy (ADT) select for decreased DRAIC expression, and higher levels of DRAIC in prostate cancer are associated with longer disease-free survival (DFS). Androgen induced androgen receptor (AR) binding to the DRAIC locus and repressed DRAIC expression. In contrast, FOXA1 and NKX3-1 are recruited to the DRAIC locus to induce DRAIC, and FOXA1 specifically counters the repression of DRAIC by AR. The decrease of FOXA1 and NKX3-1, and aberrant activation of AR, thus accounts for the decrease of DRAIC during prostate cancer progression to the CR state. Consistent with DRAIC being a good prognostic marker, DRAIC prevents the transformation of cuboidal epithelial cells to fibroblast-like morphology and prevents cellular migration and invasion. A second tumor-suppressive lncRNA PCAT29, located 20 kb downstream of DRAIC, is regulated identically by AR and FOXA1 and also suppresses cellular migration and metastasis. Finally, based on TCGA analysis, DRAIC expression predicts good prognosis in a wide range of malignancies, including bladder cancer, low-grade gliomas, lung adenocarcinoma, stomach adenocarcinoma, renal clear cell carcinoma, hepatocellular carcinoma, skin melanoma, and stomach adenocarcinoma. Implications: This study reveals a novel tumor-suppressive locus encoding two hormone-regulated lncRNAs, DRAIC and PCAT29, that are prognostic for a wide variety of cancer types. Mol Cancer Res; 13(5); 828–38. ©2015 AACR.

[1]  C. Wahlestedt.  Targeting long non-coding RNA to therapeutically upregulate gene expression , 2013, Nature Reviews Drug Discovery.

[2]  Howard Y. Chang,et al.  Control of somatic tissue differentiation by the long non-coding RNA TINCR , 2012, Nature.

[3]  Anindya Dutta,et al.  A New lncRNA, APTR, Associates with and Represses the CDKN1A/p21 Promoter by Recruiting Polycomb Proteins , 2014, PloS one.

[4]  X. Liu,et al.  Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. , 2014, Cell reports.

[5]  Ryan M. Layer,et al.  MUNC, a Long Noncoding RNA That Facilitates the Function of MyoD in Skeletal Myogenesis , 2014, Molecular and Cellular Biology.

[6]  Jindan Yu,et al.  Cooperativity and Equilibrium with FOXA1 Define the Androgen Receptor Transcriptional Program , 2014, Nature Communications.

[7]  Anindya Dutta,et al.  Long non-coding RNAs as emerging regulators of differentiation, development, and disease , 2014, Transcription.

[8]  Anindya Dutta,et al.  The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration , 2014, Genes & development.

[9]  Francesca Demichelis,et al.  PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. , 2014, Cancer research.

[10]  Zhaohui S. Qin,et al.  An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. , 2010, Cancer cell.

[11]  L. Chung,et al.  Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. , 1994, Cancer research.

[12]  The Cancer Genome Atlas Research Network,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[13]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[14]  Andreas Heger,et al.  Next-generation Sequencing of Advanced Prostate Cancer Treated with Androgen-deprivation Therapy , 2014, European urology.

[15]  F. Liu,et al.  A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. , 2014, Cancer Cell.

[16]  Ankit Malhotra,et al.  miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. , 2011, Cancer research.

[17]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[18]  M. Rosenfeld,et al.  LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs , 2013, Nature.

[19]  Ryan M. Layer,et al.  Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells , 2013, Oncogene.

[20]  Jindan Yu,et al.  Androgen receptor-independent function of FoxA1 in prostate cancer metastasis. , 2013, Cancer research.

[21]  Nathan C. Sheffield,et al.  Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity , 2012, Genome Biology.

[22]  Jordan Anaya,et al.  Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets , 2014, BMC Biology.

[23]  M. Augustus,et al.  Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer. , 2000, The Journal of urology.

[24]  Anindya Dutta,et al.  The miR-99 family regulates the DNA damage response through its target SNF2H , 2012, Oncogene.

[25]  Glen Kristiansen,et al.  Tumorigenesis and Neoplastic Progression FOXA 1 Promotes Tumor Progression in Prostate Cancer and Represents a Novel Hallmark of Castration-Resistant Prostate Cancer , 2012 .

[26]  S. Dhanasekaran,et al.  The lncRNA PCAT29 Inhibits Oncogenic Phenotypes in Prostate Cancer , 2014, Molecular Cancer Research.

[27]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[28]  O. Kallioniemi,et al.  Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. , 2000, Cancer research.

[29]  Wing-Kin Sung,et al.  Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival , 2012, Molecular and Cellular Biology.

[30]  T. Thompson,et al.  Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches , 2013, Oncogene.

[31]  I. Mills.  Maintaining and reprogramming genomic androgen receptor activity in prostate cancer , 2014, Nature Reviews Cancer.

[32]  R. Vessella,et al.  Molecular determinants of resistance to antiandrogen therapy , 2004, Nature Medicine.

[33]  L. Jia,et al.  Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions , 2012, Nucleic acids research.

[34]  John McAnally,et al.  Regulation of Insulin-Like Growth Factor Signaling by Yap Governs Cardiomyocyte Proliferation and Embryonic Heart Size , 2011, Science Signaling.

[35]  S. Vowler,et al.  Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype , 2013, Oncogene.

[36]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[37]  W. Sellers,et al.  Akt-regulated pathways in prostate cancer , 2005, Oncogene.