December 15, 2021

SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity

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featured discovery

Ahn photo Dec2021squareErin Eun-Young Ahn, Ph.D., associate professor in the Department of Pathology's Division of Molecular and Cellular Pathology and scientist in the O'Neal Comprehensive Cancer Center, is the latest winner of the Heersink School of Medicine’s Featured Discovery. This initiative celebrates important research from Heersink faculty members.

Ahn’s study, “SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity” was published in Nature Communications.

Ahn says that glioblastoma multiforme (GBM) is the most common and lethal brain tumor. Only less than 5% of patients survive more than five years after diagnosis. “However, scientists’ current knowledge of GBM biology is largely limited to several genetic mutations, so we need to achieve a better understanding of the underlying molecular mechanisms of this deadly tumor to find new therapeutic targets,” she explains.

Furthermore, Ahn says that “Recently, researchers realized that the RNA editing step involving cutting and re-joining RNA pieces, called RNA splicing, plays critical roles in GBM progression. RNA splicing is regulated by multiple RNA-binding proteins, and the amount and functions of RNA-binding proteins must be well-controlled to maintain the correct RNA editing patterns in our cells.”

In the study, Ahn and her team identified that a novel RNA-binding protein SON is abundantly present in GBM cells and alters the functions of other key RNA-binding proteins, “thereby causing abnormal patterns of RNA splicing that keep the GBM tumor cells proliferating and staying at a stem cell-like stage.” Ahn and her team showed that inhibition of SON could restore the correct RNA splicing patterns and inhibit GBM tumor growth in mouse models.

While this publication revealed how an excessive amount of SON promotes GBM tumor growth, Ahn and her team also recently identified that an insufficient amount of SON can cause a developmental disorder. Read more from UAB News about how Ahn’s work with RNA splicing is helping determine the cause behind an extremely rare disease known as Zhu-Tokita-Takenouchi-Kim syndrome.

The Heersink School of Medicine communications staff sat down with Dr. Erin Eun-Young Ahn to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

Almost 15 years ago, I was working as a postdoctoral fellow at UCSD, struggling with a new project to figure out what the “SON” protein does in our cells. At that time, no one knew about the function of the SON protein and I initially focused on how SON promotes cell cycle progression by regulating the RNA editing step, called RNA splicing. While performing this study, I was also surprised to find that some neuronal cell-specific molecules were significantly changed when I reduced the SON level, even in non-neuronal cells. I was so curious about whether SON has an important function in neuronal cell-rich organs, such as the brain. However, my postdoctoral lab did not study neurons, so I wished to be able to explore this possibility if I had my own lab. Luckily, many years later, I received an opportunity to pursue my long-time question! (Dreams come true!)

Q: What was your most unexpected finding?

We hypothesized that SON expression may be altered in brain tumors compared to normal brains. When we examined brain tumor patient samples obtained from the UAB Brain Tumor Biorepository with Dr. Yancey Gillespie’s help, we were so surprised to see the remarkable differences of SON expression in glioblastoma (GBM) samples and normal brain samples. We initially studied how increased SON level facilitates the production of PTBP1, which is an oncogenic RNA splicing factor that was well described by our UAB physician-scientist, Dr. Markus Bredel, a few years ago. However, we found that SON not only promotes PTBP1 production but also inhibits another RNA splicing factor, called RBFOX2, competing with it for RNA interaction. So, the scope of the study was unexpectedly expanded as the project moved forward.

Q: How do you feel your research will impact the science community?

In this paper, we demonstrated that SON is a novel upstream regulator of the PTBP1/PTBP2 switch. This switch involves the reduction of PBTP1 and a concurrent increase of PTBP2, which is critical for the onset of “neuronal differentiation” – the process by which early stage neuronal stem cells become functionally mature neurons. Importantly, this step is blocked in GBM, because GBM cells have too much PTBP1, which makes the tumor cells behave like stem cells. We found that if we reduced the level of SON, we could induce a series of changes in RNA splicing and restore the PTBP/PTBP2 switch. Our finding showed a novel way to restore the PTBP1/PTBP2 switch in brain tumors. We think that this finding will evoke more interest in the role of RNA splicing in brain tumors as well as neuronal differentiation and brain development.

Q: What is your research’s relevance to human disease (if applicable)?

While traditional brain tumor research has focused on a few genetic mutations, we now realize that brain tumor cells use many other non-genetic cellular pathways to maintain their ability to constantly proliferate, avoid cell death, evade the immune system and become resistant to therapies. Our finding showed that RNA-binding proteins and RNA splicing play critical roles in brain tumors and could be novel therapeutic targets. Since SON affects the functions of many RNA-binding proteins, suppressing the abnormally high level of SON in brain tumors could restore many RNA regulation steps.

Q: What do you find makes the science community here unique?

UAB’s highly collaborative environment and nurturing spirit are truly outstanding. These days, I am learning tremendously from a group of experienced researchers at the UAB O’Neal Comprehensive Cancer Center Neuro-Oncology Program to expand our brain tumor research. UAB is the perfect place for students and researchers to constantly learn from colleagues and advance science by helping each other and working together.