Expression of the stem cell transcription factor SOX2 causes prostate cancer to spread and grow faster, decreasing patient survival, according to new research at the University of Illinois Cancer Center.
“New strategies are needed to predict and overcome metastatic progression and therapy resistance in prostate cancer,” said Donald Vander Griend, PhD, a member of the Translational Oncology program, associate professor of pathology at the University of Illinois College of Medicine, and lead author of the study published in the journal Oncogene.
“One potential target is SOX2, because it is important in the survival of stem and progenitor cells, can promote stem cell gene expression, repress differentiation, and promote prostate over-growth.”
Vander Griend and his colleagues analyzed a case-control cohort of 1,028 annotated tumor specimens to test the impact of SOX2 expression. Patients harboring SOX2-positive tumors developed metastases more rapidly. Using ChlP-sequencing to analyze protein interactions with DNA, the researchers found that SOX2-binding sites within prostate cancer cells differed significantly from common stem cell pathways, suggesting that SOX2 has unique functions in prostate cancer cells.
In addition, Vander Griend said, SOX2 expression was associated with increased quantities of mitochondria and changes in glucose metabolism. Metabolomic analyses revealed SOX2-associated changes in the metabolism of purines, pyrimidines, amino acids and sugars, and the pentose phosphate pathway.
“Interestingly, when we deleted SOX2 using CRISPR, prostate cancer cells were more susceptible to standard drugs and had widespread changes in how the cells used glucose and metabolism,” Vander Griend said. “Our data supports a key role for SOX2 in metabolic reprogramming of prostate cancer cells and reveal new mechanisms to understand how SOX2 enables metastatic progression and therapy resistance.
“Furthermore, our data suggests clinical opportunities to exploit SOX2 as a biomarker for staging and imaging, as well as a potential pharmacologic target.”
About one in eight men will be diagnosed with prostate cancer in his lifetime, according to the American Cancer Society. It is estimated that about 268,490 new cases of prostate cancer will be detected in 2022, with about 34,500 men dying from the disease. Prostate cancer is more likely to develop in older men and in non-Hispanic Black men. About six cases in 10 are diagnosed in men older than the age of 65, and is rare in men under the age of 40. The average age of men at diagnosis is about 66, the ACS said.
While the disease is serious – prostate cancer is the second leading cause of cancer death in American men – most men diagnosed will not die from it. More than 3.1 million men in the U.S. who have been diagnosed with prostate cancer are alive today.
The research was supported by NCI grants R01CA178431, P30CA014599, R00CA218885 and T32CA009594, and NCATS grant UL1TR002003. Among other researchers assisting Vander Griend was fellow Cancer Center member Jonathan Coloff, PhD, a member of the Cancer Biology program and assistant professor of physiology and biophysics at the University of Illinois College of Medicine.