title: KLF6 loss of function in human prostate cancer progression is implicated in resistance to androgen deprivation.
abstract: Inactivation of the transcription factor/tumor suppressor Krüppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naïve PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy.
authors: Department of Medicine, New York University Cancer Institute, New York, USA.
authors: XiaoMei
authors: X
authors: Liu
authors: Alejandro
authors: A
authors: Gomez-Pinillos
authors: Charisse
authors: C
authors: Loder
authors: Enrique
authors: E
authors: Carrillo-de Santa Pau
authors: Ruifang
authors: R
authors: Qiao
authors: Pamela D
authors: PD
authors: Unger
authors: Ralf
authors: R
authors: Kurek
authors: Carole
authors: C
authors: Oddoux
authors: Jonathan
authors: J
authors: Melamed
authors: Robert E
authors: RE
authors: Gallagher
authors: John
authors: J
authors: Mandeli
authors: Anna C
authors: AC
authors: Ferrari
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000728:Androgens / Q000172:deficiency*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000728:Androgens; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins