The Dark Side of SOX9: How Cancer Derails a Stem Cell's Path

Tuesday - August 8 2023, 23:50 UTC - 1 year ago

Rockefeller researchers have revealed the mechanisms of how the transcription factor SOX9 can abnormally be expressed in epidermal stem cells, leading to the development of certain lethal cancers. These findings provide new insights into cancer, providing new SOX9-activated genes as potential therapeutic targets.

In the early stages, every stem cell is presented with a decisive selection. For example, during the development of skin, the embryonic epidermis starts off with a single layer of epidermal progenitor cells. These cells have to decide whether to transform into a mature epidermal cell or to opt for becoming a hair follicle cell. This critical decision, known as the fate switch, is regulated by the transcription factor known as SOX9. When SOX9 is expressed by the progenitor cell, it leads to the development of hair follicle cells. In its absence, the cell develops into an epidermal cell.

But there is a dark side to SOX9, as it has been associated with some of the most lethal cancers across the globe, such as lung, skin, head and neck, and bone cancer. In the context of skin, certain aberrant adult epidermal stem cells might unexpectedly activate SOX9, regardless of their chosen path—and never turn it off, kickstarting a process that ultimately activates cancer genes.

Scientists have never fully understood how this doomed outcome ensues at a molecular level. But now Rockefeller researchers have revealed the mechanisms behind this malignant turn of events. SOX9, it turns out, belongs to a special class of proteins that govern the transfer of genetic information from DNA to mRNA. That means it has the ability to pry open sealed pockets of genetic material, bind to previously silent genes within, and activate them. They published their results in Nature Cell Biology.

"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," says Elaine Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. "It also illuminates new SOX9-activated genes as potential therapeutic targets." .

Our genome is not an open book. In fact, it’s more like a library filled with a few billion books that are mostly under lock and key—the majority of genetic material actually lies silent within non-coding and tightly bound packets of DNA cordoned off by histone proteins in a closed state. Together the DNA and histones form what’s called closed chromatin. The genes that are packaged into this cloistered material are inaccessible to the transcription proteins, or factors, that would help it to express the genes within.

But there are a few rare keys that aren’t simply transcription factors. These "pioneer factors" can unlock those genetic packets. They possess the superpower to peer inside the closed chromatin and recognize binding sites within. They then recruit other transcription factors to help them pry open the closed chromatin and bind to receptor sites on the nucleosome, which reprograms the chromatin and activates new genes.

This normally happens during the early stages of development, when a stem cell’s fate is yet to be determined. In adult skin, SOX9 is normally associated with maintaining the identity of adult hair follicle stem cells. It’s normally suppressed in adult epidermal stem cells. But that’s not the case when it comes to basal cell and squamous cell carcinomas.

"In skin cancers, SOX9 is actually expressed at very high levels in patients yet to receive treatment and even in those who have had aggressive treatments," says László Nagy, a research associate and first author of the paper. "This suggested to us that SOX9 might be playing some other real role in cancer." .