RT Journal Article
SR Electronic
T1 The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaaw4993
DO 10.1126/scitranslmed.aaw4993
VO 11
IS 503
A1 Liu, Yuzhen
A1 Horn, Jessie L.
A1 Banda, Kalyan
A1 Goodman, Asha Z.
A1 Lim, Yiting
A1 Jana, Sujata
A1 Arora, Sonali
A1 Germanos, Alexandre A.
A1 Wen, Lexiaochuan
A1 Hardin, William R.
A1 Yang, Yu C.
A1 Coleman, Ilsa M.
A1 Tharakan, Robin G.
A1 Cai, Elise Y.
A1 Uo, Takuma
A1 Pillai, Smitha P. S.
A1 Corey, Eva
A1 Morrissey, Colm
A1 Chen, Yu
A1 Carver, Brett S.
A1 Plymate, Stephen R.
A1 Beronja, Slobodan
A1 Nelson, Peter S.
A1 Hsieh, Andrew C.
YR 2019
UL http://stm.sciencemag.org/content/11/503/eaaw4993.abstract
AB The androgen receptor is a well-known driver of prostate cancer and a common therapeutic target in this disease. Now, Liu et al. have identified an unexpected link between the androgen receptor and regulation of mRNA translation. The authors determined that the androgen receptor has a suppressive effect on protein synthesis, whereas the loss of this receptor is associated with increased initiation of translation, facilitating tumor cell proliferation. This observation helps explain the rapid growth of late-stage androgen receptor–deficient prostate cancer and provides a therapeutic opportunity through inhibition of a translation initiation complex, which the authors demonstrate in mouse models.The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.