MRC National Institute for Medical Research, London
Science for Health
A key developmental and stem cell regulator also acts in tumorigenesis
20 January 2012
Research published by NIMR scientists describes how a gene known to play a role in normal development and stem cells can contribute to the processes of transformation leading to cancer. The work is published in Cancer Research.
SOX9 is a transcription factor known to play critical roles during the development of several cell types and tissues in the embryo. It is also important for stem cell biology in a number of systems in the adult. The misregulation of developmental genes is often associated with cancer. Certain cancers are thought to have a stem cell origin or to depend on a stem cell (or ‘tumour initiating cell’) population for their maintenance and/or reoccurrence after therapy. It is therefore not surprising that, over the last few years, high levels of SOX9 have been associated with several types of cancer. However, in most cases this was merely a correlation, with no knowledge of whether SOX9 is causative and, if so, the molecular mechanisms involved.
Ander Matheu (pictured), a postdoctoral scientist working in Robin Lovell-Badge’s lab in NIMR's Division of Stem Cell Biology and Developmental Genetics, has now shown with functional and clinical data that SOX9 has a broad and important role in tumorigenesis. In collaboration with labs in Spain and Norway, SOX9 was found to be overexpressed in a wide range of human cancers, and the level of expression correlated with malignant character and progression. Moreover, gain of SOX9 copy number is detected in some primary colorectal cancers. In both mouse and human cell line studies, and with in vivo mouse tumour models, SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence and collaborate with other oncogenes in neoplastic transformation.
Although a high level of SOX9 by itself does not produce tumours, this was found to facilitate tumour growth and progression, whilst inactivation of SOX9 reduced tumorigenicity. Mechanistically, it was found that SOX9 directly binds and activates the promoter of the polycomb protein Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and INK4a-ARF in clinical samples. Taken together, these findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly in colorectal cancer.
Finding a target gene for SOX9 with a clear role in oncogenesis is important for mechanistic understanding of how SOX9 impacts on cancer, but it may also allow screens for therapeutic agents that could interfere with tumour formation or progression.
Robin Lovell-Badge
Original article
Matheu A, Collado M, Wise C, Manterola L, Cekaite L, Tye AJ, Canamero M, Bujanda L, Schedl A, Cheah KS, Skotheim RI, Lothe RA, Lopez de Munain A, Briscoe J, Serrano M, Lovell-Badge R. (2012)
Oncogenicity of the developmental transcription factor Sox9
Cancer Research epub ahead of print. PubMed abstract.
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