Narla G et al. (2005) A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 65: 1213–1222

One of the strongest risk factors for prostate cancer is family history of disease, but the predisposing genetic factors are unknown. KLF6 suppresses cell growth through p53-independent transactivation of p21, and mutations leading to the inactivation or loss of KLF6 have been linked to other human cancers. Narla et al. investigated the possibility that inherited KLF6 mutations or polymorphisms exist that may increase prostate cancer risk.

Direct sequencing of genomic DNA isolated from blood revealed one very frequent polymorphism, IVSδA; IVS1–27 G > A. To identify a possible association between this single nucleotide polymorphism and prostate cancer risk, germline DNA was genotyped from 3,411 geographically diverse men from three independent institutions, including 1,253 sporadic cancer patients, 882 familial cancer patients and 1,276 control men. It was found that there was a significant association between IVSδA and cancer in both sporadic and familial cancer.

Using KLF6 minigene constructs in cultured cells, it was established that KLF6 was alternatively spliced, that there was an overabundance of KLF6 splice variants to wild type in tumor tissue, and that IVSδA was consistently associated with enhanced KLF6 alternative splicing and variant protein expression. Complementary DNA sequence analysis confirmed the presence of three alternatively spliced KLF6 gene transcripts. These findings led to the suggestion that IVSδA effected a change in wild-type KLF6 tumor suppressor gene expression and function. A splicing enhancer motif prediction program showed that the IVSδA allele generates a functional SRp40 binding sequence, and studies with minigene constructs showed that spliced forms of KLF6 antagonize wild-type KLF6 effects on p21 and cell growth.

The authors note that the critical balance between the growth-suppressive and growth-promoting forms of KLF6 can profoundly influence prostate biology and cancer risk.