Siam Rania, Harada Ryoko, Cadieux Chantal, Battat Robert, Vadnais Charles, Nepveu Alain
Goodman Cancer Center, McGill University, 1160 Pine Avenue West, Room 410, Montreal, Quebec H3A 1A3, Canada.
Mol Cancer. 2009 Aug 5;8:60. doi: 10.1186/1476-4598-8-60.
Lats1 (large tumor suppressor 1) codes for a serine/threonine kinase that plays a role in the progression through mitosis. Genetic studies demonstrated that the loss of LATS1 in mouse, and of its ortholog wts (warts) in Drosophila, is associated with increased cancer incidence. There are conflicting reports, however, as to whether overexpression of Lats1 inhibits cell proliferation. CUX1 is a transcription factor that exists in different isoforms as a result of proteolytic processing or alternative transcription initiation. Expression of p110 and p75 CUX1 in transgenic mice increases the susceptibility to cancer in various organs and tissues. In tissue culture, p110 CUX1 was shown to accelerate entry into S phase and stimulate cell proliferation.
Genome-wide location arrays in cell lines of various cell types revealed that Lats1 was a transcriptional target of CUX1. Scanning ChIP analysis confirmed that CUX1 binds to the immediate promoter of Lats1. Expression of Lats1 was reduced in cux1-/- MEFs, whereas it was increased in cells stably or transiently expressing p110 or p75 CUX1. Reporter assays confirmed that the immediate promoter of Lats1 was sufficient to confer transcriptional activation by CUX1. Lats1 was found to be overexpressed in tumors from the mammary gland, uterus and spleen that arise in p110 or p75 CUX1 transgenic mice. In tissue culture, such elevated LATS1 expression did not hinder cell cycle progression in cells overexpressing p110 CUX1.
While inactivation of Lats1/wts in mouse and Drosophila can increase cancer incidence, results from the present study demonstrate that Lats1 is a transcriptional target of CUX1 that can be overexpressed in tumors of various tissue-types. Interestingly, two other studies documented the overexpression of LATS1 in human cervical cancers and basal-like breast cancers. We conclude that, similarly to other genes involved in mitotic checkpoint, cancer can be associated with either loss-of-function or overexpression of Lats1.
Lats1（大肿瘤抑制因子1）编码一种丝氨酸/苏氨酸激酶，其在有丝分裂进程中发挥作用。遗传学研究表明，小鼠中LATS1及其在果蝇中的同源基因wts（疣）缺失与癌症发病率增加有关。然而，关于Lats1过表达是否抑制细胞增殖存在相互矛盾的报道。CUX1是一种转录因子，由于蛋白水解加工或选择性转录起始而以不同的异构体形式存在。转基因小鼠中p110和p75 CUX1的表达增加了各种器官和组织对癌症的易感性。在组织培养中，p110 CUX1被证明可加速进入S期并刺激细胞增殖。
对各种细胞类型的细胞系进行全基因组定位分析表明，Lats1是CUX1的转录靶点。扫描染色质免疫沉淀分析证实CUX1与Lats1的直接启动子结合。在cux1 - / - 小鼠胚胎成纤维细胞中Lats1的表达降低，而在稳定或瞬时表达p110或p75 CUX1的细胞中其表达增加。报告基因分析证实Lats1的直接启动子足以赋予CUX1转录激活作用。在p110或p75 CUX1转基因小鼠发生的乳腺、子宫和脾脏肿瘤中发现Lats1过表达。在组织培养中，这种升高的LATS1表达并不妨碍过表达p110 CUX1的细胞的细胞周期进程。
虽然小鼠和果蝇中Lats1 / wts的失活可增加癌症发病率，但本研究结果表明Lats1是CUX1的转录靶点，可在各种组织类型的肿瘤中过表达。有趣的是，另外两项研究记录了LATS1在人类宫颈癌和基底样乳腺癌中的过表达。我们得出结论，与参与有丝分裂检查点的其他基因类似，癌症可能与Lats1的功能丧失或过表达有关。
