Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximate promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximate promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

The plan of the paper is as follows. In section 2, we develop the non-local spin density functional for E,,. It is then applied to atoms in section 3. ~h~ applications to s-d transfer energy for 3d transition elements are discussed in section 4. Finally, in section 5, we Present a correlation energy functional which isThe exchange-correlation functional of Langreth and Mehl [Phys. Rev. B28, 1809 (1983)l is generalized to include spin dependence. It is then applied to the calculation of ground-state and electron removal energies in atoms. A functional for the correlation energy alone is also given, for use in cases where exchange can be calculated exactly. combined with exact exchange calculations.

The previous work by Langreth and Perdew and by Langreth and Mehl for calculation of the exchange-correlation density functional is put on the same sort of basis as standard calculations for the uniform system by the approximate calculation of the following terms which go beyond the random-phase approximation (RPA): the second-order exchange term and self-energy corrections of similar order. It is found when both local [local-density approximation (LDA)] and nonlocal terms are included, that the net effect of these additional terms is found to be small, so that the RPA previously used is a much better approximation than previously supposed. Evidence is presented that suggests for localized systems that the leading non-RPA terms in the LDA represent mostly a spurious self-interaction error which is removed when the nonlocal beyond-RPA terms are included as well; it is suggested that this error can be most simply avoided by just using the RPA alone for both the local and nonlocal contributions, as done in the simple approximation suggested by Langreth and Mehl [Phys. Rev. 8 2$, 1809(1983].

We proposed that in multiferroics, there exists a third long-range order besides the electric polarization and magnetic order. This long-range order reduces the symmetry of the spatial part of the wave functions of electrons. Thus the cancellation in the "spin-current" model can be avoided. As a result, the expectation value of electric polarization will be larger by an order of magnitude. We have derived a distinct form of electric polarization P ជ ϳ −Q ϫ ͑ŝ j ϫ ŝ j+1 ͒, where Q ជ is the wave vector of this long-range order.