PRMT1 accelerates cell proliferation, migration, and tumor growth by upregulating ZEB1/H4R3me2as in thyroid carcinoma

Abstract

Thyroid carcinoma (TC) represents the most prevalent malignancy of the endocrine system. Protein arginine methyltransferase 1 (PRMT1) is a critical member of the protein arginine methyltransferase family in mammals and is involved in multiple biological processes. This study aimed to investigate the function of PRMT1 in TC. In the present study, human TC cell lines (8505C, CAL62, and BCPAP) and a normal human thyroid cell line Nthy-ori 3-1 were employed. Small interfering RNA targeting PRMT1 was used to knock down PRMT1 expression in 8505C cells, and PRMT1 overexpression plasmids were transfected into BCPAP cells. Cell viability was assessed using a CCK-8 and colony formation assays. Apoptosis was measured using flow cytometry and TUNEL assays. Cell migration was assessed using wound healing and Transwell assays. Reverse transcription-quantitative PCR was used to determine the mRNA expression levels of PRMT1. Western blotting was used to detect the protein expression levels of PRMT1, E-cadherin, vimentin, H4R3me2as, and zinc-finger E homeobox-binding 1 (ZEB1). Notably, PRMT1 expression was elevated in TC (P<0.01). PRMT1 knockdown inhibited TC cell proliferation and migration and concurrently enhanced migration. Furthermore, PRMT1 knockdown suppressed tumor growth and metastasis in a mouse model of TC. PRMT1 downregulation increased E-cadherin expression and decreased the expression of vimentin, H4R3me2as, and ZEB1 in the TC cells and the mouse model of TC. Conversely, PRMT1 overexpression had the opposite effect on TC malignant characteristics (P<0.05). These findings suggest that PRMT1 knockdown inhibited TC malignancy by downregulating H4R3me2as/ZEB1, thereby highlighting novel therapeutic targets and diagnostic markers for the management of TC.

Oligomerization of protein arginine methyltransferase 1 and its effect on methyltransferase activity and substrate specificity

“…PRMT1, a type I enzyme, is the predominant isoform in mammalian cells accounting for ~85% of total protein arginine methylation (Tang et al, 2000 ). Knockout of PRMT1 in mice results in embryo lethality (Pawlak et al, 2000 ) while altered PRMT1 protein expression has been reported in various types of cancer, including lung, breast, bladder, and pancreatic cancers (Feng et al, 2023 ; Filipović et al, 2019 ; He et al, 2020 ; Song et al, 2020 ; Wang et al, 2019 ; Yoshimatsu et al, 2011 ), as well as in idiopathic pulmonary fibroses (Lambers et al, 2019 ; Zakrzewicz et al, 2014 ; Zakrzewicz et al, 2015 ) and asthma (Park et al, 2021 ; Sun et al, 2017 ). The catalytic core of PRMT1 contains a Rossman fold that binds the cofactor AdoMet, a beta‐barrel that is thought to be involved in substrate binding (Schapira & Ferreira de Freitas, 2014 ), and a dimerization arm.…”