SOX in development and disease

As stem cells are needed not only to build our bodies during development, but also to maintain tissue function during adulthood, it is of great importance to the organism to maintain their integrity. However, stem cells also pose a threat, as oncogenic mutations can transform them or their progeny to malignant cells giving rise to cancer. Many SOX members have been defined as master regulators of stem cell maintenance, cell fate specification and differentiation. How SOX factors regulate stem cell function across different lineages and also how they can contribute to disease protection following oncogenic insult are key questions in this thesis.

In Paper I we investigate how SOX2 can regulate both cell type specific and common features of stem cells from four different tissues of two germ layers. Using ChIP-seq and RNA-seq analysis we find that although SOX2 binds some common targets, SOX2 binding is mostly cell type specific. This specificity coincides with motif enrichment of common or cell type specific transcription factors. We further show that SOX2 can interact with, and functionally regulate gene expression together with these transcription factors. Moreover, we also find that isolated peak regions can act as cis-regulatory modules (CRMs) to activate germ layer specific and common expression in zebrafish.

In Paper II we ask how adult stem cells of the brain can evade oncogenic transformation and elicit an appropriate tumor suppressor response. We find that the functionally related SOX5, SOX6 and SOX21 (SOX5/6/21) are induced in neural stem cells after oncogenic expression, and that this upregulation is required for the cells to repress tumor development. We also demonstrate that the expression levels of SOX5/6/21 are significantly lower in human tissue from highly malignant glioma compared to glioma of lower malignancy grade, and that re-establishing SOX5/6/21 expression in human glioma cells leads to a re-gain in tumor suppressor function and response. We further show that these functional characteristics are at least in part dependent on the ability of SOX21 to stabilize the protein levels of the tumor suppressor p53.

In Paper III we expand on the findings demonstrated in Paper II and ask whether stem cells of different origins and with different characteristics use SOX21 in a similar manner to establish protection from oncogenic transformation. Using the stomach as a model system, we find stem cell expression of SOX21 in both mouse and human tissue, and that the SOX21 mRNA levels are significantly downregulated in human gastric cancer compared to normal tissue. By overexpressing SOX21 in human gastric cancer cell lines, we find that proliferation decreases and apoptosis is induced, but only in cell lines expressing p53. We further show that wt p53 levels are increased after SOX21 expression and we speculate that this could at least in part be responsible for the increase in the anti-tumorigenic response.

Together, the work in this thesis highlights SOX transcription factors as important regulators of the vastly different but connected processes of stem cell maintenance and stem cell protection. Performing these functions SOX proteins use both their well-studied ability to bind and regulate gene expression together with partner factors, but also an ability to bind and affect proteins at a post-translational level.

List of scientific papers

I. Daniel W. Hagey, Susanne Klum, Idha Kurtsdotter, Cécile Zaouter, Danijal Topcic, Olov Andersson, Maria Bergsland and Jonas Muhr. SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs. PLOS Genetics. 2018 Feb 12;14(2).
https://doi.org/10.1371/journal.pgen.1007224

II. Idha Kurtsdotter, Danijal Topcic, Alexandra Karlén, Bhumica Singla, Daniel W. Hagey, Maria Bergsland, Peter Siesjö, Monica Nistér, Joseph W. Carlson, Veronique Lefebvre, Johan Holmberg and Jonas Muhr. SOX5/6/21 prevent oncogene-driven transformation of brain stem cells. Cancer Research. 2017 Sep 15;77(18):4985-4997.
https://doi.org/10.1158/0008-5472.CAN-17-0704

III. Idha Kurtsdotter, Maria Bergsland, Daniel W. Hagey, Danijal Topcic, Fredrik Klevebro, Magnus Nilsson and Jonas Muhr. SOX21 induces cell cycle arrest and apoptosis in gastric cancer cells. [Manuscript]