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Alternative splicing of Krüppel-like factor 6 (KLF6) enriched in human androgen-deprived prostate cancer (PC).
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| Zeitschriftentitel: | Journal of Clinical Oncology |
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| Personen und Körperschaften: | , , , , , , , , , , , |
| In: | Journal of Clinical Oncology, 30, 2012, 15_suppl, S. e15191-e15191 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
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| Schlagwörter: |
| Zusammenfassung: | <jats:p> e15191 </jats:p><jats:p> Background: Inactivation of KLF6 by mutations and alternative splicing has been implicated in PC. However, there are significant discrepancies among human PC studies concerning the prevalence and significance of KLF6 mutations, and the prevalence of splice variants (SVs) has not been established. The objective of this study was to assess the prevalence and role of KLF6 splicing in human PC progression. Methods: Human specimens were obtained from the tissue banks of three institutions. Representative epithelium of 74 frozen PC specimens [25 primary hormone-naïve (HN) PCs, 21 primary hormone-deprived (HD) PCs, 6 castrate-resistant metastases] and 22 normal prostates (NPs) were microdissected. KLF6 cDNA was amplified by PCR, cloned and sequenced in both forward and reverse directions and compared to the KLF6 GenBank sequence. The transcriptional activity of KLF6 SVs was evaluated in co-transfection assays with a p21-reporter, and their effect on LNCaP cell growth was determined by MTT assays. Results: Sixteen different SVs were identified: 13 were novel; 14 affected the DNA binding domain (DBD) and were transcriptionally inactive. The incidence of SVs was increased in PC versus NP (75% vs 45%; p=0.01) and in HD-PC versus HN-PC (90% vs 64%; p=0.04) HD-PC were significantly enriched in SVs lacking the DBD. Forced expression of dysfunctional KLF6 SVs increased growth of LNCaP cells in androgen-depleted media. Conclusions: KLF6 SVs lacking p21-reporter transactivation activity occur in NP epithelium but are markedly increased in incidence, variety and level of expression in PC tissues that survive androgen-deprivation. This enrichment may enable resistance to hormone therapy and a proliferative advantage under castrate conditions. </jats:p> |
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| Umfang: | e15191-e15191 |
| ISSN: |
0732-183X
1527-7755 |
| DOI: | 10.1200/jco.2012.30.15_suppl.e15191 |