RAS oncogenic signal upregulates EZH2 in pancreatic cancer
Abstract
The neoplastic transformation by mutant RAS is thought to require remodeling of expression of an entire set of genes. However, the underlying mechanism for initiation of gene expression remodeling in tumorigenesis remains elusive. This study was aimed to define the oncogenic role of EZH2, a histone modifier protein that is induced by oncogenic mutant RAS, using pancreatic cancers of transgenic rats exogenously expressing human mutant RAS. Immunohistochemical observation of preneoplastic or cancerous lesions in the animal model suggested that upregulation of Ezh2 protein is an initiating event in pancreatic carcinogenesis. MEK-inhibition or Elk-1-knockdown downregulated EZH2, and MEK-inhibition or EZH2-knockdown restored expression of a tumor suppressor, RUNX3 in human and rat pancreatic cancer cells activated by the oncogenic RAS. Furthermore, Elk-1- or EZH2-knockdown inhibited growth of the cancer cells. These results strongly suggested that the oncogenic RAS upregulates EZH2 through MEK-ERK signaling, resulted in downregulation of tumor suppressors including RUNX3 in pancreatic carcinogenesis.
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Higher MEK-ERK pathway activity has been associated with overexpression of Ezh2.
“On the other hand, increased activation of the MEK-ERK pathway has been linked to Ezh2 overexpression48.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [48]
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- Authors
- Fujii, S., Fukamachi, K., Tsuda, H., Ito, K., Ito, Y., & Ochiai, A.
- Affiliations
- Nagoya City University (JP)
- Nagasaki University (JP)
- National University of Singapore (SG)
- National Cancer Centre Japan (JP)
- Corresponding author
- Ochiai, Atsushi
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 417
- Issue
- 3
- Pages
- 1074-1079
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2000183036
- Cited by
- 38
- References
- 20
- Citations by year
- 2025: 2 · 2024: 2 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 7 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (21590453)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- EZH2, oncogenic Ras, pancreatic cancer, pancreatic carcinogenesis, MEK/ERK signaling, Elk-1, RUNX3, histone methyltransferase, tumor suppressor downregulation, transgenic rats
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Humans, Pancreatic Neoplasms, Histone-Lysine N-Methyltransferase, Proto-Oncogene Proteins, Transcription Factors, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), ras Proteins, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Core Binding Factor Alpha 3 Subunit, Rats, Rats, Transgenic, Polycomb Repressive Complex 2
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