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Key transcription factor for stem cell differentiation linked to cancer

Stem cells are unspecialised cells, defined by their capacity for self-renewal and ability to differentiate into a variety of somatic cell types. Early in development, stem cells undergo a fate choice, mediated by the transcription factors involved in the decision-making process. A new study published in Nature Cell Biology, has shown that one such pioneer transcription factor, SOX9, is responsible for more than just singular stem cell fate decisions. SOX9 has been implicated in the development of skin cancer thorough its ability to send stem cells down a cancer-associated differentiation route, rather than their planned specialisation.

An important decision

During skin development, stem cells can differentiate into either hair follicle cells or mature epidermal cells. This decision relies on the presence or absence of SOX9, respectively, expression of which is normally downregulated after the decision has been made.

In this study, researchers at Rockefeller University found that development of skin cancers, such as basal cell carcinoma, can occur due to re-activated and sustained SOX9 expression. In this situation, embryonic hair follicle cells grow into follicle-like tumour masses which lack hair linages. SOX9 overexpression has also been previously associated with development of several other cancer types including glioma, lung and colorectal cancers. This expression is generally associated with poor patient outcomes. However, the exact tumorigenic mechanism remains to be established.

Identity hijacking

Pioneer transcription factors, such as SOX9, have the unique ability to recognise and access their cognate binding motif even in compacted and repressed chromatin. This allows the opening and remodelling of the chromatin landscape to alter gene expression, potentially changing a cell’s identity. This fate-switching ability allows pioneer factors to not only perturb their own target nucleosome, but to also recruit co-factors to epigenetically modify surrounding histones.

It is currently unknown how a pioneer transcription factor is able to simultaneously induce and silence gene expression, however this study furthers understanding of how this could be possible. Researchers found that a dual function model is favoured, whereby a pioneer factor actively hijacks and redistributes shared co-factors to achieve cost-effective and coordinated fate switching from one lineage to another (Figure 1).

Figure 1. Working model for how SOX9 achieves cell fate switching
Pioneer factor SOX9 indirectly silences the epidermal fate by competing against co-factors and other transcription factors (TFs) from active embryonic epidermal stem cell (EpdSC) enhancers. SOX9 then binds directly to key hair follicle stem cell (HFSC) enhancers, bringing with it the hijacked chromatin remodelling machinery, instead activating the hair follicle fate. SOX9 target TFs include RUNX1, whose footprints appear to participate in the delayed activation of basal cell carcinoma (BCC) cancer genes. This leads to fate switching to a BCC state, downstream of the EpdSC-to-HFSC fate transition. Adapted from Yang et al. 2023.

A targetable finding

Outside of the hair follicle budge microenvironment, proliferating cells with sustained SOX9 expression activate downstream target transcription factors, such as those encoding the RUNX family that drive further dynamic changes in the chromatin landscape.

Taken together, these findings begin to explain how and why sustained re-activation of a pioneer factor involved in embryonic fate decisions frequently leads to cancer. This highlights a potential opportunity for the therapeutic targeting of SOX9 and its downstream targets to treat various cancer types, including basal cell carcinoma.