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Background   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.    Results  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.    Conclusion  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 .

Transcriptional activation of the Lats1 tumor suppressor gene in tumors of CUX1 transgenic mice