Abstract
BC200 is a long non-coding RNA (lncRNA) that has been implicated in the regulation of protein synthesis, yet whether dysregulation of BC200 contributes to the pathogenesis of human diseases remains elusive. In this study, we show that BC200 is upregulated in breast cancer; among breast tumor specimens there is a higher level of BC200 in estrogen receptor (ER) positive than in ER-negative tumors. Further experiments show that activation of estrogen signaling induces expression of BC200. To determine the significance of ER-regulated BC200 expression, we knockout (KO) BC200 by CRISPR/Cas9. BC200 KO suppresses tumor cell growth in vitro and in vivo by expression of the pro-apoptotic Bcl-xS isoform. Mechanistically, BC200 contains a 17-nucleotide sequence complementary to Bcl-x pre-mRNA, which may facilitate its binding to Bcl-x pre-mRNA and recruitment of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a known splicing factor. Consequently, hnRNP A2/B1 interferes with association of Bcl-x pre-mRNA with the Bcl-xS-promoting factor Sam68, leading to a blockade of Bcl-xS expression. Together, these results suggest that BC200 plays an oncogenic role in breast cancer. Thus, BC200 may serve as a prognostic marker and possible target for attenuating deregulated cell proliferation in estrogen-dependent breast cancer.
Highlights
Long non-coding RNAs provide a new perspective to the central dogma of gene expression, where DNA is transcribed into RNAs that do not code for protein, in addition to protein-coding mRNAs.[1]
LncRNAs are involved in the regulation of various biological processes, such as genome imprinting, gene regulation, chromatin organization and alternative splicing.[3]
They can serve as master gene regulators through various mechanisms,[4] and their deregulation may lead to a variety of diseases such as diabetes, neurodegenerative disorders, cardiovascular disease and cancer.[5]
Summary
Long non-coding RNAs (lncRNAs) provide a new perspective to the central dogma of gene expression, where DNA is transcribed into RNAs that do not code for protein, in addition to protein-coding mRNAs.[1]. The rest of them are non-coding RNAs, including microRNAs and lncRNAs. Since there is a lack of a satisfactory method for the classification of lncRNAs, they are arbitrarily considered to be longer than ~ 200 nucleotides and can go up to over 100 kb.[2] LncRNAs are involved in the regulation of various biological processes, such as genome imprinting, gene regulation, chromatin organization and alternative splicing.[3] they can serve as master gene regulators through various mechanisms,[4] and their deregulation may lead to a variety of diseases such as diabetes, neurodegenerative disorders, cardiovascular disease and cancer.[5] For example, a number of lncRNAs have been implicated in different aspects of tumorigenesis such as tumor cell growth and proliferation, invasion and metastasis, and they can function as oncogenes or tumor suppressor genes.[6]. We report that BC200 is transcriptionally induced by estrogen in breast cancer cells, and it prevents apoptosis by modulating alternative splicing of a member of the Bcl-2 family, Bcl-x.12
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