Author ORCID Identifier

0000-0001-5038-694X

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Keping Xie, M.D., Ph.D.

Committee Member

Menashe Bar-Eli, Ph.D.

Committee Member

Zhen Fan, M.D.

Committee Member

Jian Gu, Ph.D.

Committee Member

Craig D. Logsdon, Ph.D.

Committee Member

Shao-Cong Sun, Ph.D.

Abstract

Protein arginine methyltransferase 1 (PRMT1) is the major arginine methyltransferase, which catalyzes the addition of one or two methyl groups to the arginine residues of its substrate proteins. The best-known substrate for PRMT1 is histone, while more and more non-histone proteins are now found to be methylated by PRMT1. Dysregulation of PRMT1 is reported in several human cancer types. However, its biological roles in human pancreatic cancer initiation and development are still unclear. In the first part of this study, I found that the expression level of PRMT1 was elevated in both human and mouse pancreatic cancer tissues in immunohistochemistry analysis. The further functional studies demonstrated a pro-tumorigenic role of PRMT1 in several pancreatic cancer cell lines and mouse models.

In the second part of this study, several heat shock protein 70 (HSP70) family members were found to interact with PRMT1 in co-immunoprecipitation assays. Furthermore, using in vitro methylation assay and mass spectrometry analysis, I revealed that HSP70 was a novel methylation substrate of PRMT1, and conserved arginine residues were identified as the methylation sites. By using HSP70 knockout cells generated by CRISPR/Cas9 system and a series of wildtype and methylation sites mutant HSP70 expression vectors, I demonstrated that PRMT1-mediated arginine methylation was essential for the drug resistance function of HSP70 in pancreatic cancer cells.

Collectively, my results not only elucidate the important role of PRMT1 in pancreatic cancer pathogenesis, but also suggest a novel underlying mechanism of HSP70-mediated drug resistance to chemotherapeutic agents. Therefore, targeting PRMT1-HSP70 axis could be a new therapeutic regimen for pancreatic cancer.

Keywords

pancreatic cancer, arginine methylation, PRMT1, protein-protein interaction, HSP70, drug resistance

Available for download on Wednesday, August 08, 2018

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