Cancer-associated regulation of alternative splicing.
Alternative splicing of pre-mRNA increases the diversity of protein functions. Here we show that about half of all active alternative splicing events in ovarian and breast tissues are changed in tumors, and many seem to be regulated by a single factor; sequence analysis revealed binding sites for the RNA binding protein FOX2 downstream of one-third of the exons skipped in cancer. High-resolution analysis of FOX2 binding sites defined the precise positions relative to alternative exons at which the protein may function as either a silencer or an enhancer. Most of the identified targets were shifted in the same direction by FOX2 depletion in cell lines as they were in breast and ovarian cancer tissues. Notably, we found expression of FOX2 itself is downregulated in ovarian cancer and its splicing is altered in breast cancer samples. These results suggest that the decreased expression of FOX2 in cancer tissues modulates splicing and controls proliferation.
Venables
Julian P
JP
Laboratoire de génomique fonctionnelle de l'Université de Sherbrooke, Sherbrooke, Québec, Canada.
Klinck
Roscoe
R
Koh
ChuShin
C
Gervais-Bird
Julien
J
Bramard
Anne
A
Inkel
Lyna
L
Durand
Mathieu
M
Couture
Sonia
S
Froehlich
Ulrike
U
Lapointe
Elvy
E
Lucier
Jean-François
JF
Thibault
Philippe
P
Rancourt
Claudine
C
Tremblay
Karine
K
Prinos
Panagiotis
P
Chabot
Benoit
B
Elela
Sherif Abou
SA
D017398:Alternative Splicing; D020816:Amino Acid Motifs; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry; D017422:Sequence Analysis, DNA
D016601:RNA-Binding Proteins