ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor

Abstract

The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR’s ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.DOI: http://dx.doi.org/10.7554/eLife.13964.001

Arginine Methylation: The Coming of Age

“…The ETS transcription factor ERG is frequently translocated in prostate cancer (TMPRSS2: ERG), and it promotes prostate cancer formation in mice (Afar et al, 2001). PRMT5 was identified as an interactor of ERG and shown to be recruited to androgen receptor target genes for cancer progression (Mounir et al, 2016). Furthermore, it transcriptionally regulates the expression of the androgen receptor coding gene by serving as a co-factor for transcription factors Sp1 and Brg1 (Deng et al, 2016).…”

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

“…PRMT5 is a putative oncogene and its upregulation correlates with tumor progression, as shown for breast, ovarian and prostate cancer (Hsu et al, 2011;Mounir et al, 2016;. PRMT5 is the major type II PRMT and mice deficient in this gene are not viable (Tee et al, 2010).…”

Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG

“…These seemingly contradictory findings suggest that ERG modulation of AR activity is more complex than previously appreciated, an unsurprising notion given the vast heterogeneity of the AR transcriptional landscape and the degeneracy within the ARE consensus sequence (23)(24)(25). Furthermore, physical interaction of ERG with AR has been documented by mass spectrometry (26) and coimmunoprecipitation (22).…”