The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Liu, Yuzhen; Horn, Jessie L.; Banda, Kalyan; Goodman, Asha Z.; Lim, Yiting; Jana, Sujata; Arora, Sonali; Germanos, Alexandre A.; Wen, Lexiaochuan; Hardin, William Royce; Yang, Yu Chi; Coleman, Ilsa M.; Tharakan, Robin; Cai, Elise Y.; Uo, Takuma; Pillai, Smitha P.S.; Corey, Eva; Morrissey, Colm; Chen, Yu; Carver, Brett S.; Plymate, Stephen R.; Beronja, Slobodan; Nelson, Peter S.; Hsieh, Andrew C.

doi:10.1126/scitranslmed.aaw4993

Cited by 54 publications

(70 citation statements)

References 46 publications

(59 reference statements)

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“…The EIF2 pathway regulates translation initiation. Our results are consistent with other studies reporting AR-mediated transcriptional control of translation initiation (20). We now show that translation initiation is mediated by chromatin interactions involving the AR and FOXA1.…”

Section: Resultssupporting

confidence: 93%

The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer

Ramanand¹,

Chen²,

Yuan³

et al. 2020

Journal of Clinical Investigation

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Oncology, Taiho, Pfizer, and Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers, and PI3K/ AKT pathway inhibitors (no personal income). JDB was named an inventor, with no financial interest, for US patent 8,822,438 ("Methods and compositions for treating cancer"). He has been the co-investigator or principal investigator of many industry-sponsored clinical trials.

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Section: Resultssupporting

confidence: 93%

The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer

Ramanand¹,

Chen²,

Yuan³

et al. 2020

Journal of Clinical Investigation

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“…1d, 3a–e). We utilized ribosome profiling 43,44 , to analyze WTAP -dependent effects on mRNA translation. This analysis yielded 1055 genes that were translationally changed without significant alterations to mRNA levels following WTAP KO, with 738 up and 317 downregulated (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The profiling methodology was based largely on protocols described by Ingolia and Hsieh and colleagues 43,44 . Wild-type and WTAP knockdown HEL cells were utilized to generate both ribosome protected RNA libraries as well as alkaline digested total RNA libraries using the ARTseq Ribosome Profiling Kit (Illumina).…”

Section: Methodsmentioning

confidence: 99%

N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

et al. 2019

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Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

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“…Our analysis of regulons revealed potential druggable pathways related to sex hormones in distinct tumor subsets: the androgen receptor pathway was significantly activated in class 3 tumors, although there was no enrichment for male patients in this group. In a recent study, low levels of the androgen receptor have been linked to increased translation and tumor proliferation in prostate cancer 50 , and the high levels observed in class 3 could therefore have a protective effect. Class 2a was dominated by high levels of ESR2 regulon activity, while 2b was dominated by high levels of ESR1 and PGR, indicating that hormonal receptor activity may play a pivotal role in disease development.…”

Section: Discussionmentioning

confidence: 98%

An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer

Lindskrog

Prip

Lamy

et al. 2020

Preprint

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The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Cited by 54 publications

References 46 publications

The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer

The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer

N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer

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