DiFeo Analisa, Martignetti John A, Narla Goutham
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Drug Resist Updat. 2009 Feb-Apr;12(1-2):1-7. doi: 10.1016/j.drup.2008.11.001. Epub 2008 Dec 18.
The Krüppel-like zinc finger transcription factor (KLF6) gene encodes a family of proteins generated through alternative splicing involved in the regulation of cancer development and progression. Alternative splicing of the KLF6 gene results in the production of at least four alternatively spliced isoforms, two of which are extensively discussed in this review. The full length form of the KLF6 gene is a tumor suppressor gene that is frequently inactivated by loss of heterozygozity (LOH), somatic mutation, and/or decreased expression in human cancer. While the exact mechanisms underlying KLF6's tumor suppressor roles are not completely known, a number of highly relevant, overlapping pathways have been described: transactivation of p21 in a p53-independent manner, reduction of cyclin D1/cdk4 complexes via interaction with cyclin D1, inhibition of c-Jun proto-oncoprotein activities, decreased VEGF expression, and induction of apoptosis. Kruppel-like factor 6 splice variant 1 (KLF6-SV1) is an oncogenic splice variant of the KLF6 tumor suppressor gene that is specifically overexpressed in a number of human cancers. Increased KLF6-SV1 expression is associated with poor prognosis in prostate, lung, and ovarian cancer. Furthermore, KLF6-SV1 has been shown to be biologically active, antagonizing the tumor suppressor function of KLF6 and promoting tumor growth and dissemination in both ovarian and prostate cancer models. In addition, a common germline polymorphism in the KLF6 gene associated with increased prostate cancer risk in a large multi-institutional study of 3411 men results in increased expression of KLF6-SV1. Furthermore, recent studies have demonstrated that targeted reduction of KLF6-SV1 results in the induction of spontaneous apoptosis in cell culture, synergizes with chemotherapeutic agents like cisplatin, and results in significant tumor regression in vivo. Combined, these data make the KLF6 gene family a compelling therapeutic target for both the treatment of localized as well as metastatic cancer.
Krüppel样锌指转录因子（KLF6）基因编码一类通过可变剪接产生的蛋白质家族，这些蛋白质参与癌症发生和发展的调控。KLF6基因的可变剪接导致至少产生四种可变剪接异构体，本文将重点讨论其中两种。KLF6基因的全长形式是一种肿瘤抑制基因，在人类癌症中经常因杂合性缺失（LOH）、体细胞突变和/或表达降低而失活。虽然KLF6作为肿瘤抑制因子发挥作用的确切机制尚不完全清楚，但已描述了一些高度相关且相互重叠的途径：以p53非依赖方式反式激活p21、通过与细胞周期蛋白D1相互作用减少细胞周期蛋白D1/细胞周期蛋白依赖性激酶4（cdk4）复合物、抑制c-Jun原癌蛋白活性、降低血管内皮生长因子（VEGF）表达以及诱导细胞凋亡。Krüppel样因子6剪接变体1（KLF6-SV1）是KLF6肿瘤抑制基因的一种致癌剪接变体，在多种人类癌症中特异性过表达。KLF6-SV1表达增加与前列腺癌、肺癌和卵巢癌的不良预后相关。此外，在卵巢癌和前列腺癌模型中，KLF6-SV1已被证明具有生物学活性，可拮抗KLF6的肿瘤抑制功能并促进肿瘤生长和扩散。此外，在一项对3411名男性进行的大型多机构研究中，与前列腺癌风险增加相关的KLF6基因常见种系多态性导致KLF6-SV1表达增加。此外，最近的研究表明，靶向降低KLF6-SV1可在细胞培养中诱导自发凋亡，与顺铂等化疗药物协同作用，并在体内导致显著的肿瘤消退。综合这些数据，KLF6基因家族成为治疗局限性和转移性癌症极具吸引力的治疗靶点。
