In the early stages of development, stem cells are faced with a crucial decision. For instance, during skin development, embryonic epidermis begins as a layer of epidermal progenitor cells. These cells must choose between becoming mature epidermal cells or transitioning into hair follicle cells. This pivotal decision is controlled by the transcription factor SOX9. The presence of SOX9 leads to the development of hair follicle cells, while its absence results in epidermal cells.

Figure 1. SOX9-Induced Lesions Resembling Basal Cell Carcinoma in Epidermal Tissue. (Credit: Yihao Yang, Fuchs Lab)

Figure 1 displays a microscopic image of epidermal tissue, with distinct color-coded features. In green, the lesions induced by the presence of SOX9 are depicted, resembling basal cell carcinoma. These abnormal areas of differentiation are highlighted in red, signifying disrupted cellular development. The blue marks represent the cell nuclei, providing a clear visualization of the affected regions. The image captures the impact of SOX9 activation on the epidermal tissue, showcasing its role in initiating lesions with characteristics similar to basal cell carcinoma.

However, SOX9 has a darker side, as it is associated with a range of deadly cancers, including lung, skin, head and neck, and bone cancer. In skin, some adult epidermal stem cells deviate from their intended path and express SOX9, initiating a process that activates cancer-related genes and ultimately leads to cancer development.

Understanding the molecular mechanisms underlying this cancer-related outcome has been a challenge. Recent research by Rockefeller scientists has shed light on these mechanisms. SOX9 belongs to a unique group of proteins that play a role in transferring genetic information from DNA to mRNA. This implies that SOX9 can open previously sealed pockets of genetic material, interact with dormant genes, and activate them. The findings were published in Nature Cell Biology.

Elaine Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, highlights the significance of this discovery. She explains that this insight provides a new perspective on how cancer disrupts the decision-making process of stem cells, preventing them from forming normal tissue. Additionally, the study identifies genes activated by SOX9 as potential targets for therapeutic interventions.

The regulation of gene expression is a complex process. The majority of genetic material is "closed" within DNA and tightly bound histone proteins, forming closed chromatin. Transcription factors, including special "pioneer factors," have the ability to unlock these closed genetic packets. Pioneer factors can penetrate closed chromatin, recognize binding sites, and recruit other factors to activate genes, which usually occurs during early development.

SOX9 is typically associated with maintaining the identity of adult hair follicle stem cells and is suppressed in adult epidermal stem cells. However, in conditions like basal cell and squamous cell carcinomas, SOX9 is reactivated in adult epidermal stem cells.

To understand the sequence of events leading to this reactivation, the researchers engineered mice with inducible SOX9 expression. By activating SOX9, they observed a progressive reprogramming of epidermal stem cells, resembling basal cell carcinoma over time. The researchers discovered that SOX9 orchestrates this fate switch by repurposing nuclear machinery from active genes to dormant hair follicle genes, enabling them to be activated.

The intricate process involves SOX9 acting as a pioneer factor, uniquely capable of accessing closed chromatin. As SOX9 remains overly active in various deadly cancers, the researchers aim to explore ways to disrupt its role in cell proliferation. By understanding how SOX9 interacts with proteins and genes during malignancy, they hope to uncover potential drug targets for these cancers.

Source: The Rockefeller University

Cite this article:

Hana M (2023), Epigenetic Key Reveals Path to Common Deadly Cancers, AnaTechmaz, pp.489