Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread.
Prostate cancer is a leading cause of cancer death in men. Risk prognostication, treatment stratification, and the development of rational therapeutic strategies lag because the molecular mechanisms underlying the initiation and progression from primary to metastatic disease are unknown. Multiple lines of evidence now suggest that KLF6 is a key prostate cancer tumor suppressor gene including loss and/or mutation in prostate cancer tumors and cell lines and decreased KLF6 expression levels in recurrent prostate cancer samples. Most recently, we identified a common KLF6 germ line single nucleotide polymorphism that is associated with an increased relative risk of prostate cancer and the increased production of three alternatively spliced, dominant-negative KLF6 isoforms. Here we show that although wild-type KLF6 (wtKLF6) acts as a classic tumor suppressor, the single nucleotide polymorphism-increased splice isoform, KLF6 SV1, displays a markedly opposite effect on cell proliferation, colony formation, and invasion. In addition, whereas wtKLF6 knockdown increases tumor growth in nude mice >2-fold, short interfering RNA-mediated KLF6 SV1 inhibition reduces growth by approximately 50% and decreases the expression of a number of growth- and angiogenesis-related proteins. Together, these findings begin to highlight a dynamic and functional antagonism between wtKLF6 and its splice variant KLF6 SV1 in tumor growth and dissemination.
Narla
Goutham
G
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
DiFeo
Analisa
A
Yao
Shen
S
Banno
Asoka
A
Hod
Eldad
E
Reeves
Helen L
HL
Qiao
Rui F
RF
Camacho-Vanegas
Olga
O
Levine
Alice
A
Kirschenbaum
Alexander
A
Chan
Andrew M
AM
Friedman
Scott L
SL
Martignetti
John A
JA
D017398:Alternative Splicing; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D054278:Embryonal Carcinoma Stem Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014162:Transfection
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators