New Insights into Cancer Development and Potential Therapeutic Targets Revealed
Researchers at Rockefeller University have made a groundbreaking discovery about the role of the transcription factor SOX9 in both normal skin development and cancer. SOX9 is responsible for guiding stem cells in the epidermis to differentiate into either epidermal cells or hair follicle cells. However, when SOX9 is misregulated, it can lead to the development of certain cancers.
The researchers found that SOX9 belongs to a special class of proteins called “pioneer factors,” which have the ability to open sealed portions of the genetic material and activate previously silent genes. This discovery provides new insights into the development of cancer and potential therapeutic targets.
During the early stages of skin development, stem cells face a decisive choice between becoming mature epidermal cells or hair follicle cells. This decision is regulated by the transcription factor SOX9. If SOX9 is expressed, the stem cell develops into a hair follicle cell. If it is absent, the stem cell becomes an epidermal cell.
However, the study also revealed a dark side to SOX9, as it has been associated with various deadly cancers, including lung, skin, head and neck, and bone cancer. In certain cases, adult epidermal stem cells activate SOX9, leading to the activation of cancer genes and the development of cancer.
Traditionally, it has been unclear how this molecular process occurs. However, the Rockefeller researchers discovered that SOX9 has the capability to open closed chromatin, which contains silent genes. This allows SOX9 to activate these genes and initiate the development of cancer.
Elaine Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, explains, “Our discovery provides new insights into how cancer derails a stem cell’s carefully tuned decision-making process, thereafter making it impossible for it to make normal tissue. It also illuminates new SOX9-activated genes as potential therapeutic targets.”
The researchers describe pioneer factors like SOX9 as rare keys that can unlock sealed portions of the genetic material. These pioneer factors can recognize binding sites within the closed chromatin and recruit other transcription factors to activate genes.
The study also involved the creation of transgenic mice that contained an activatable form of SOX9 in their epidermal stem cells. By activating SOX9, the researchers observed the progressive reprogramming of these stem cells, leading to the development of basal cell carcinoma-like structures.
Additionally, the researchers found that SOX9 hijacks the nuclear machinery of active genes and brings it to silent hair follicle genes, enabling the fate switch from epidermal cells to hair follicle cells. This complicated process is only possible because SOX9 is a pioneer factor with the ability to access closed chromatin.
Given that SOX9 is overly active in many deadliest cancers worldwide, the researchers are now focused on identifying ways to intervene in its role in cell proliferation. By understanding how SOX9 interacts with other proteins and target genes during malignancy, they hope to uncover new drug targets for these cancers.
The findings of this study were published in Nature Cell Biology and provide valuable insights into the mechanisms underlying cancer development and potential avenues for therapeutic intervention.
Reference: “The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates” by Yihao Yang, Nicholas Gomez, Nicole Infarinato, Rene C. Adam, Megan Sribour, Inwha Baek, Mélanie Laurin, and Elaine Fuchs, 24 July 2023, Nature Cell Biology.
DOI: 10.1038/s41556-023-01184-y