Pancreatic cancer remains one of the deadliest malignancies worldwide. As the 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is only about 3% of patients, PDAC is very difficult to treat surgically worldwide. A better understanding of the biology of PDAC at the molecular level is needed to develop new treatment methods.
In a recent article published in Cancer Scienceresearchers from Tokyo Medical and Dental University (TMDU) have identified a new target gene that has strong clinical implications in PDAC cases.
Previous studies have shown that cancer cells express high levels of a special enzyme, histone H3K4 methyltransferase, which is encoded by SETD1A gene. This enzyme regulates gene expression by adding a methyl chemical group to the histone proteins (basic structural components of chromatin) of specific target genes through a process called methylation. However, the mechanism causing overexpression of this enzyme and its effect on cancer cells remain unclear. After histone methylation, target genes are activated. This is particularly significant if SETD1A target genes can promote cancer development and progression. Therefore, TMDU researchers became interested in understanding the role SETD1A overexpression in PDAC.
Although previous work has shown this SETD1A is overexpressed in various cancers such as gastric and lung cancer, which are specific molecular phenomena SETD1A are not understood in PDAC. SETD1A target genes in PDAC have also not yet been identified.”
Takeshi Ishii, lead author
Researchers observed high levels SETD1A expression in 51.4% of the human PDAC samples they analyzed. They determined that too SETD1A was an independent prognostic factor for disease-free survival, that is, after tumor resection, patients with high SETD1A levels live in a disease-free state for a shorter period of time than those with low SETD1A levels. These results show clinical relevance SETD1A expression in PDAC.
They then used artificially cultured PDAC cells to see how they changed SETD1A expression would affect cell behavior. When they overexpressed themselves SETD1A levels increased both cell growth and cell migration ability. In another set of PDAC cells, the researchers used molecular techniques to interfere SETD1A expression and then analyzed other genes that were affected by it. “Using a technique called RNA sequencing, we examined overall gene expression after the knockdown SETD1A and found that another gene known as RUVBL1 was expressed at lower levels,” explains lead author Shinji Tanaka.
Other works indicated this SETD1A can methylate nearby histones RUVBL1 gene and activate its gene expression. Knocking down RUVBL1 expression in PDAC cells had similar biological effects to those observed previously with SETD1A interference. “Analysis of survival rates revealed that PDAC patients with high SETD1A and RUVBL1 levels had worse overall survival, suggesting that their co-expression is an important prognostic biomarker for this cancer,” says Takeshi Ishii.
The results of the study provide deeper insight into the meaning SETD1A and RUVBL1 expression in PDAC and may offer crucial details to help clinicians make critical treatment decisions for patients suffering from this serious disease.
Tokyo Medical and Dental University
Link to journal:
Ishii, T., et al. (2022) Identification of a novel SETD1A histone methyltransferase target and clinical significance in pancreatic cancer. Cancer Science. doi.org/10.1111/cas.15615.
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