Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis.

Singh, R; Gupta, S C; Peng, W-X; Zhou, N; Pochampally, R; Atfi, A; Watabe, K; Lu, Z; Mo, Y-Y

Singh, R; Gupta, S C; Peng, W-X; Zhou, N; Pochampally, R; Atfi, A; Watabe, K; Lu, Z; Mo, Y-Y.

Afiliación

Singh R; Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Gupta SC; Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Peng WX; Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Zhou N; Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China.
Pochampally R; System Biosciences, Mountain View, CA, USA.
Atfi A; Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Watabe K; Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Lu Z; Cancer Biology, Wake Forest School of Medicine, Bermuda Run, NC, USA.
Mo YY; Department of Endocrinology, PLA General Hospital, Beijing, China.

Cell Death Dis ; 7(6): e2262, 2016 06 09.

Article en En | MEDLINE | ID: mdl-27277684

RESUMEN

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.

Asunto(s)

Empalme Alternativo/genética; Neoplasias de la Mama/genética; Neoplasias de la Mama/patología; Carcinogénesis/patología; ARN Largo no Codificante/metabolismo; Proteína bcl-X/genética; Empalme Alternativo/efectos de los fármacos; Apoptosis/efectos de los fármacos; Apoptosis/genética; Secuencia de Bases; Carcinogénesis/efectos de los fármacos; Carcinogénesis/genética; Línea Celular Tumoral; Proliferación Celular/efectos de los fármacos; Proliferación Celular/genética; Supervivencia Celular/efectos de los fármacos; Supervivencia Celular/genética; Estrógenos/farmacología; Femenino; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Técnicas de Inactivación de Genes; Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo; Humanos; Regiones Promotoras Genéticas/genética; Unión Proteica; Isoformas de Proteínas/genética; Isoformas de Proteínas/metabolismo; Precursores del ARN/metabolismo; ARN Largo no Codificante/genética; ARN Mensajero/genética; ARN Mensajero/metabolismo; Transcripción Genética/efectos de los fármacos; Regulación hacia Arriba/efectos de los fármacos; Regulación hacia Arriba/genética; Proteína bcl-X/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Empalme Alternativo / Proteína bcl-X / ARN Largo no Codificante / Carcinogénesis Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Female / Humans Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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