Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis.
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.
Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
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R
Singh
Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
S C
SC
Gupta
Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China.
W-X
WX
Peng
System Biosciences, Mountain View, CA, USA.
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N
Zhou
Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
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R
Pochampally
Department of Biochemistry, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
A
A
Atfi
Cancer Biology, Wake Forest School of Medicine, Bermuda Run, NC, USA.
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K
Watabe
Department of Endocrinology, PLA General Hospital, Beijing, China.
Z
Z
Lu
Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Y-Y
YY
Mo
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D004967:Estrogens; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D020033:Protein Isoforms; D012322:RNA Precursors; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D051020:bcl-X Protein; C000609640:long non-coding RNA BC200, human