Narla Goutham, Difeo Analisa, Reeves Helen L, Schaid Daniel J, Hirshfeld Jennifer, Hod Eldad, Katz Amanda, Isaacs William B, Hebbring Scott, Komiya Akira, McDonnell Shannon K, Wiley Kathleen E, Jacobsen Steven J, Isaacs Sarah D, Walsh Patrick C, Zheng S Lilly, Chang Bao-Li, Friedrichsen Danielle M, Stanford Janet L, Ostrander Elaine A, Chinnaiyan Arul M, Rubin Mark A, Xu Jianfeng, Thibodeau Stephen N, Friedman Scott L, Martignetti John A
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Cancer Res. 2005 Feb 15;65(4):1213-22. doi: 10.1158/0008-5472.CAN-04-4249.
Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.
前列腺癌是男性癌症死亡的主要且日益普遍的原因。尽管家族病史是最强的前列腺癌风险因素之一，提示存在遗传成分，但易感基因因素仍不清楚。我们首先表明KLF6是一种在前列腺癌中发生体细胞失活的肿瘤抑制因子，自那时起，其功能丧失在前列腺癌细胞系和其他人类癌症中得到进一步证实。野生型KLF6而非患者来源的突变体通过p21的p53非依赖性反式激活抑制细胞生长。在此我们表明，在一项对3411名男性的三机构研究中得到证实的种系KLF6单核苷酸多态性与男性前列腺癌相对风险增加显著相关，无论其家族病史如何。这种与前列腺癌相关的等位基因产生一个新的功能性SRp40 DNA结合位点，并增加三种可变剪接的KLF6亚型的转录。KLF6变异蛋白KLF6-SV1和KLF6-SV2定位于细胞质错误，拮抗野生型KLF6功能，导致p21表达降低和细胞生长增加，并且在肿瘤组织与正常前列腺组织中上调。因此，这些结果首次确定了一种自我编码的肿瘤抑制基因失活的新机制，并将一种相对常见的单核苷酸多态性与可变剪接的调节以及一种主要人类癌症的风险增加联系起来。
