Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen‐independent status

Abstract

BACKGROUND Coactivator‐associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of the androgen receptor (AR). It is involved in the regulation of the biologic functions of the AR. It remains to be determined whether CARM1 is involved in prostatic carcinogenesis. METHODS The expression of CARM1 in normal prostate epithelium, high‐grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone‐independent prostate carcinoma, using immunohistochemical methods. RESULTS Cell staining was observed in the cytoplasm and the nucleus. In 66 patients without previous hormonal treatment, the percentage of cells that stained positively for CARM1 in benign prostate tissue specimens (mean values: cytoplasm, 23%; nucleus, 16%) was statistically significantly less than the percentage of positively stained cells in PIN (mean values: cytoplasm, 56%; nucleus, 30%; P < 0.001) and in prostatic adenocarcinoma specimens (mean values: cytoplasm, 79%; nucleus, 53%; P < 0.001). The difference between adenocarcinoma and PIN also was statistically significant (P < 0.001). The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001). In the 12 patients with androgen‐independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment. Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion. CONCLUSIONS The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen‐independent prostate carcinoma. Since CARM1 is functionally different from most other transcriptional coactivators of the AR, it may serve as a new target for the treatment of hormone‐independent prostate carcinoma. Cancer 2004. © 2004 American Cancer Society.

Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene

“…Thus, ACTR͞AIB1 is amplified and͞or overexpressed in various carcinomas, including 30% of breast tumors of various grades, where it affects both estrogen-receptorand E2F-dependent transcriptions (18,40,41). Similarly, CARM1 was recently found to be overexpressed in androgen-independent prostate carcinomas (48). Here, we conducted a pilot experiment on breast tumor specimens of various grades and found cooverexpression of CCNE1, ACTR, and CARM1 genes in grade-3 tumors.…”

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

“…The arginine methyltransferase, CARM1/PRMT4, has been shown to regulate important cellular processes such as pluripotency maintenance (16,32), differentiation (6,15,17), splicing (18), and transcriptional activation (10 -14), as well as tumor manifestation and progression (33,34). However, the methyltransferase activity of this coactivator has been linked with only a few cases of transcriptional activation, muscle and thymocyte differentiation, and tumor progression.…”

Alternative Splicing Yields Protein Arginine Methyltransferase 1 Isoforms with Distinct Activity, Substrate Specificity, and Subcellular Localization

“…For example, the fact that PRMT1 and CARM1 can act as coactivators of nuclear receptors makes them likely candidates to be overexpressed in hormone-dependent cancers, including breast cancer (2). Indeed, it has been found that CARM1 overexpression correlates with androgen independence in human prostate carcinomas (73,74). It has also been observed that increased methylation of a PRMT6 substrate correlated with breast tumors of higher metastatic potential (75,76).…”