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1.
Proc Natl Acad Sci U S A ; 113(5): 1273-8, 2016 Feb 02.
Article in English | MEDLINE | ID: mdl-26768845

ABSTRACT

Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its ß-transducin repeat-containing protein (TrCP)-mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer.


Subject(s)
CCAAT-Enhancer-Binding Proteins/metabolism , Colonic Neoplasms/genetics , RNA, Long Noncoding/physiology , CCAAT-Enhancer-Binding Proteins/chemistry , Cell Line, Tumor , Epigenesis, Genetic , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Lysine/metabolism , Nerve Tissue Proteins/metabolism , Proteolysis , Ubiquitin-Protein Ligases , Ubiquitination , Up-Regulation
2.
Biochem Biophys Res Commun ; 459(1): 29-35, 2015 Mar 27.
Article in English | MEDLINE | ID: mdl-25701787

ABSTRACT

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a multi-functional protein involved in transcription, mRNA splicing, mRNA stabilization and translation. Although hnRNP K has been suggested to play a role in the development of many cancers, its molecular function in colorectal cancer has remained elusive. Here we show that hnRNP K plays an important role in the mitotic process in HCT116 colon cancer cells. Furthermore, we demonstrate that hnRNP K directly transactivates the NUF2 gene, the product of which is a component of the NDC80 kinetochore complex and which is known to be critical for a stable spindle microtubule-kinetochore attachment. In addition, knockdown of both hnRNP K and NUF2 caused failure in metaphase chromosome alignment and drastic decrease in the growth of colon cancer cells. These results suggest that the hnRNP K-NUF2 axis is important for the mitotic process and proliferation of colon cancer cells and that this axis could be a target for the therapy of colon cancer.


Subject(s)
Cell Cycle Proteins/metabolism , Colonic Neoplasms/pathology , Heterogeneous-Nuclear Ribonucleoprotein K/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Colonic Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Heterogeneous-Nuclear Ribonucleoprotein K/genetics , Humans , Mice, Inbred BALB C , Mitosis , Promoter Regions, Genetic , Up-Regulation , Xenograft Model Antitumor Assays
3.
Sci Rep ; 3: 1305, 2013.
Article in English | MEDLINE | ID: mdl-23419616

ABSTRACT

Mammalian genomes encode numerous antisense non-coding RNAs, which are assumed to be involved in the regulation of the sense gene expression. However, the mechanisms of their action and involvement in the development of diseases have not been well elucidated. The ANA/BTG3 protein is an antiproliferative protein whose expression is downregulated in prostate and lung cancers. Here we show that an antisense transcript of the ANA/BTG3 gene, termed ASBEL, negatively regulates the levels of ANA/BTG3 protein, but not of ANA/BTG3 mRNA and is required for proliferation and tumorigenicity of ovarian clear cell carcinoma. We further show that knockdown of ANA/BTG3 rescues growth inhibition caused by ASBEL knockdown. Moreover, we demonstrate that ASBEL forms duplexes with ANA/BTG3 mRNA in the nucleus and suppresses its cytoplasmic transportation. Our findings illustrate a novel function for an antisense transcript that critically promotes tumorigenesis by suppressing translation of the sense gene by inhibiting its cytoplasmic transportation.


Subject(s)
Carcinoma/genetics , Cell Transformation, Neoplastic , Ovarian Neoplasms/genetics , Proteins/genetics , RNA, Antisense , Apoptosis/genetics , Biological Transport , Carcinoma/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Cell Nucleus/metabolism , Cytoplasm/metabolism , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Gene Order , Humans , Ovarian Neoplasms/metabolism , Proteins/metabolism , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Transcription, Genetic
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