Era Cobani

Genomic Characterization of Protein Methyltransferases Identifies Therapeutic Targets for Cancer Treatment

Authors: Era Cobani (biological sciences), 2021 Winner ðŸ†, Zeng-Quan Yang (principal investigator), Yuanyuan Jiang (postdoctoral fellow), Rui Wang (visiting scholar from China)

Faculty mentor: Zeng-Quan Yang

Abstract

Protein methyltransferases (PMTs) are a class of enzymes involved in epigenetic regulation that catalyze the transfer of one or more methyl groups to lysine (K) and arginine (R) residues on histone and non-histone proteins. PMTs are classified into two subfamilies: protein lysine methyltransferases (PKMT) and protein arginine methyltransferases (PRMT). Recent genomic studies have shown that the genes involved in epigenetic regulation are altered in cancers at unexpectedly high frequencies, suggesting that certain PMTs may be driver genes in cancer development and progression. In this study, we performed a genomic meta-analysis that identified the association of copy number alterations (amplification, homozygous deletion) and mutations of 68 PMT genes (51 PKMTs and 17 PRMTs) with clinical features such as tumor grade, survival and prognosis in 32 cancer types. Utilizing the data from more than 10,000 tumor samples in TCGA data set via cBioPortal and other oncogenomic databases, we identified 24 PMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 3 with homozygous deletion, and 13 with somatic mutation. Loss-of-function analysis was conducted to examine PMT candidates with important roles in the growth and survival of more than 10 cancer cells. As a result, we identified two genes: SETDB1 and PRDM10 as candidate therapeutic targets. PRDM10 is lost in a significant number of cancers such as sarcoma, melanoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, etc., while SETDB1 is significantly amplified in cancers such as breast invasive carcinoma, uterine cancer, bladder urothelial carcinoma, liver hepatocellular carcinoma, etc. RT-qPCR and Western blots were conducted to measure the mRNA expression and protein levels of these two oncogenes in a panel of more than 10 cancer cell lines. In brief, this study provides a comprehensive analysis and gives insight into novel potential therapeutic targets for certain cancers.

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