Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis

Abstract

Aberrant expression of regulators for epigenetics is involved in tumorigenesis. There is an urgent need to identify and characterize regulators concerned with epigenetics in the early stages of hepatocarcinogenesis. In the present study, we found that the expression of coactivator-associated arginine methyltransferase 1 (CARM1), a histone methyltransferase that functions as a cofactor for nuclear hormone receptors and several transcription factors, was elevated in adenomas and aberrant in carcinomas during hepatocellular carcinogenesis. In addition to RNA expression, immunohistochemical staining of liver sections revealed that CARM1 was highly expressed in the nucleus of tumor marker glutathione S-transferase placental form (GST-P)-positive foci. Neoplastic transformation of GST-P-positive foci guides the formation of hepatocellular carcinomas. CARM1 expression was not elevated in GST-P-negative regions. Furthermore, a luciferase reporter analysis revealed that CARM1 activated the Gst-p promoter in H4IIE, a hepatocellular carcinoma cell line. This activation was mediated by the enhancer element responsible for the carcinogenic-specific expression of Gst-p and nuclear factor E2-related factor 2. Knockdown of Carm1 by shRNA in H4IIE cells inhibited cell proliferation. These findings suggest that aberrantly expressed CARM1 in tumor marker-positive cells promotes tumorigenesis in the early stages of hepatocarcinogenesis.

Differential CARM1 Isoform Expression in Subcellular Compartments and among Malignant and Benign Breast Tumors

“…CARM1 is overexpressed in a variety of cancer types [ 11 – 13 ], has been identified as an oncogenic client protein of Hsp90 in K562 leukemia cells [ 14 ] and regulates tumor metastasis by methylation of BAF155 in MDA-MB-231 breast cancer cells [ 6 ]. However, the function of CARM1 in oncogenesis and cancer progression remains unknown, and conflicting evidence supports two opposing roles for CARM1 in proliferation [ 15 – 17 ] and differentiation [ 11 , 18 ].…”

Epigenetic Aberrations in Multiple Myeloma

“…PRMT4 and PRMT5, for instance, could play a role in supporting MM pathogenesis. PRMT4 (also known as CARM1) is overexpressed in several solid tumors, including breast, prostate cancer, and hepatocellular carcinoma [ 62 , 63 , 64 ]. PRMT4 catalyzes the addition of methyl groups to arginine 17 and 26 of histone H3, as well as to non-histone proteins.…”

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma

“…CARM1 overexpression has been reported in many cancer types including breast 12 , prostate 13 , and liver 14 and a role for CARM1 in oncogenesis in these and other cancer types has been proposed, though its mechanism is not clear 9 , 15 , 16 . Originally identified as a co-activator of steroid hormone receptor-mediated transcription, CARM1 has been shown to interact with several nuclear receptors including the estrogen and androgen receptors, and it may mediate oncogenic effects in cancers driven by these pathways 17 .…”