2023-08-03 21:55:38
In the cells there is a transcription factor, called SOX9, which is implicated in lung, skin, head and neck, and bone cancers/File
Every stem cell in the body faces a fateful choice. During skin development, for example, the embryonic epidermis begins as a single layer of epidermal progenitor cells. Their choice is to become a mature epidermal cell or to be a hair follicle cell.
This so-called fate change is governed by the so-called “SOX9 transcription factor”. If the progenitor cell expresses SOX9, hair follicular cells develop. If it doesn’t, the epidermal cells do. Researchers from the United States studied it and found what it has to do with the development of aggressive cancer.
SOX9 has a dark side, as it is implicated in many of the world’s deadliest cancers, including lung, skin, head and neck, and bone cancers.
In the skin, some aberrant adult epidermal stem cells subsequently activate SOX9 despite the chosen pathway, and never deactivate it, initiating a process that ultimately activates cancer genes.
This image was captured by US scientists. They are lesions (in green) similar to basal cell carcinoma induced by SOX9 in the epidermis. Abnormal differentiation is shown in red, and blue marks cell nuclei/ CREDIT Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Rockefeller University
Scientists have never fully understood how this fatal outcome occurs at the molecular level. But now researchers from Rockefeller University and the Howard Hughes Medical Institute in the United States have revealed the mechanisms behind this malignant turn of events.
It turns out that SOX9 belongs to a special class of proteins that govern the transfer of genetic information from DNA to mRNA. This means that it has the ability to open sealed bags of genetic material, bind to previously silenced genes, and activate them. The results were published in Nature Cell Biology.
“Our discovery provides new insights into how cancer derails a stem cell’s carefully tuned decision-making process, thereafter rendering it unable to make normal tissue,” said Elaine Fuchs, director of the Robin Chemers Neustein Laboratory of Cell Biology and Development. of Mammals and research leader.
“It also illuminates new genes activated by SOX9 as possible therapeutic targets”, highlighted the researcher. In other words, the results allow us to glimpse options for the development of future cancer treatments.
Rockefeller University scientist Elaine Fuchs led research that provided new insights into how cancer derails a stem cell’s carefully tuned decision-making process/ Rockefeller University
The human genome is not an open book. In fact, it’s more like a library filled with billions of books, most of which are locked away: Most of the genetic material sits quietly inside tightly bound, non-coding packages of DNA, cordoned off by histone proteins in the closed state.
DNA and histones form what is called “closed chromatin”. The genes packed into this cloistered material are inaccessible to the transcription proteins, or factors, that would help express the genes they contain. But there are a few rare keys that are not simple transcription factors.
These “pioneering factors” can unlock those gene packages, as they have the superpower to peer inside closed chromatin and recognize the binding sites within. They then recruit other transcription factors to help open the closed chromatin and bind to receptor sites on the nucleosome, reprogramming the chromatin and activating new genes.
This usually occurs in the early stages of development, when the fate of a stem cell has not yet been determined. In adult skin, SOX9 is normally associated with maintenance of adult hair follicle stem cell identity. It is normally suppressed in adult epidermal stem cells. But this is not the case in basal and squamous cell carcinomas.
The study in the US pointed to possible therapeutic targets to which future therapies for different cancers could be directed (Gettyimages)
“In the context of disease, SOX9 is reactivated in adult epidermal stem cells,” explained Yihao Yang, first author of the study.
How this step-by-step process unfolded was unknown until now, says Yang: “In vitro reprogramming happens really fast, in 48 hours. With such a short time window, it’s hard to get good resolution of the sequence of events.”
To find out, the researchers engineered mice that contained a copy of SOX9 that could be activated in their adult epidermal stem cells when the rodents were fed doxycycline, a drug that induced transgenic SOX9.
SOX9 is a gene in humans that codes for a protein: the SOX9 transcription factor/File
“In adult tissues, decisions that were easily made in embryogenesis are strictly suppressed so that adult stem cells stick to their specific task,” Fuchs explained.
However, SOX9 release turned out to be a potent influencer that progressively reprogrammed epidermal stem cells to new destinations. “By expressing only this SOX9 transcription factor,” Yang commented, “we were able to induce basal cell carcinoma-like structures at week six. At week 12, we started to see lesions resembling human basal cell carcinoma.”
Simultaneously, they kept track of the epigenetic process taking place behind the scenes. In the first two weeks, SOX9 turned off the genes in the epidermal stem cells. Reversing their normal state, they began to activate the genes of the hair follicle stem cells.
It is believed that by identifying how the proteins that interact with the SOX9 factor and its genes change during malignancy, better tools for cancer control could be found/Archive
Searching for the mechanism, the researchers discovered that to achieve this fate change, SOX9 hijacked the nuclear machinery of active epidermal genes and brought this stolen equipment to the silent genes of the hair follicle. It then turned to other transcription factors to open the locked chromatin and bind to the silent genes, activating them.
“When SOX9 could not be regulated, the stem cells did not produce hair, but instead continued to proliferate and activate various new transcription factors, ultimately leading to a basal cell carcinoma state,” Fuchs explained.
This complicated back and forth between identities was only possible because SOX9 is a pioneering factor, according to Yang. “Only a pioneer factor has the ability to access closed chromatin,” she noted.
Because the SOX9 factor is overactive in many highly aggressive cancers, researchers are looking for ways to intervene in its role in the proliferation of these cells. “By identifying how the proteins that interact with SOX9 and their target genes change during malignancy, we hope to advance the discovery of new drug targets for these cancers,” Fuchs said.
Keep reading:
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