Androgen and androgen receptor (AR) are essential for male germ cell development and reproductive functions, but many of their mechanisms are poorly understood. This study identifies a novel gene CMTM3, can affect the transactivity of AR. Similar to human CMTM1 and 2, CMTM3 also has the highest expression level in testes at the mRNA level. Furthermore, CMTM3 represses AR transactivation and has inhibitory effects on prostate-specific antigen (PSA) expression in LNCaP cells at both mRNA and protein levels without affecting AR expression. Interestingly, human CMTM2 is tightly linked to CMTM3 in chromosome and shares similar structural characteristics as well as expression pattern, while mouse Cmtm2a (ARR19) interacts directly with AR to inhibit its transactivation by co-translocating into the nucleus in the presence of androgen and recruiting HDAC [8]. Further experiments are necessary to elucidate the mechanisms by which CMTM3 affects AR transactivation.
CMTM3 is a leucine-rich protein containing one putative leucine zipper and two "LXXLL" AR binding motifs. Proteins such as L7 [14] and JEM-1 [15] containing a leucine zipper-like motif, and other proteins such as NRIF3 [16] and p160 family [17] possessing ‘‘LXXLL” motifs have been previously reported to function as co-regulators of nuclear receptors. The detailed mechanism by which CMTM3 interacts with AR still requires further studies, so it is essential to construct mutated forms of CMTM3, such as dele-tion of LXXLL and/or LZ motifs, to identify the critical structures for its functions.
CMTM3 may play an integral role in the development and progression of prostate cancer. AR is involved in prostate cancer [18] and this study shows CMTM3 is a novel gene that can affect the transactivation of AR and consequently inhibit PSA expression. Moreover, CMTM3 is located on chromosome 16q22, which is usually deleted in prostate cancer [19]. Therefore, it will be interesting to study CMTM3 expression levels in prostate cancer, and to determine the influence of CMTM3 on the growth of prostate cancer cells. These future studies will help understand the mechanisms underlying the development and progress of prostate cancer.
In conclusion, CMTM3 is highly expressed in testes and can repress AR transactivation. In particular, the expression pattern of CMTM3 in male reproductive organs postulates its role in AR-regulated male reproduction. Further studies of CMTM3, for example, with null mutants via knockout mice, may provide strong insight into the physiological functions of CMTM3 in the male reproductive system.
