Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance

Shukla, Shipra; Cyrta, Joanna; Murphy, Diane K.; Walczak, Edward; Ran, Leili; Agrawal, Praveen; Xie, Yuanyuan; Chen, Yuedan; Wang, Shangqian; Zhan, Yu; Li, Dan; Wong, Elissa W.P.; Sboner, Andrea; Beltran, Himisha; Mosquera, Juan Miguel; Sher, Jessica; Cao, Zhen; Wongvipat, John; Koche, Richard P.; Gopalan, Anuradha; Zheng, Deyou; Rubin, Mark A.; Scher, Howard I.; Chi, Ping; Chen, Yu

doi:10.1016/j.ccell.2017.10.008

Cited by 75 publications

(95 citation statements)

References 66 publications

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“…Consequently, the binding motif of Hnf4g is the most significantly enriched transcription factor motif in the promoters of genes that are specifically upregulated in those tumor cells that lack a CSC phenotype ( Fig EV4B). This suggests that Hnf4g is playing a role in gene regulation even in transformed cancer cells, which is in line with recent reports on other cancer types, which revealed that dysregulated Hnf4g is associated with pancreatic (Klein et al, 2018), prostate (Shukla et al, 2017), and lung cancer (Wang et al, 2018). Overall, these observations illustrate the importance of system-wide interrogation and the power of integrative analyses to uncover novel biology related to intestinal homeostasis.…”

Section: Hnf4g Drives Enterocyte Differentiationsupporting

confidence: 89%

Integrative multi‐omics analysis of intestinal organoid differentiation

Lindeboom

Voorthuijsen

Oost

et al. 2018

Molecular Systems Biology

118

120

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Intestinal organoids accurately recapitulate epithelial homeostasis in vivo, thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi‐omics framework on stem cell‐enriched and stem cell‐depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription‐driven. Integrating absolute mRNA and protein copy numbers revealed post‐transcriptional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell‐type‐specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium.

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Section: Hnf4g Drives Enterocyte Differentiationsupporting

confidence: 89%

Integrative multi‐omics analysis of intestinal organoid differentiation

Lindeboom

Voorthuijsen

Oost

et al. 2018

Molecular Systems Biology

118

120

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“…In summary, we have shown that HOXC4 and HOXC6 regulate critical genes affecting prostate cancer proliferation. In addition, we showed colocalization of HOXC4 and HOXC6 at HOXB13 sites that are also bound by FOXA1 and AR, which have been previously linked to regulation of prostate cancer cell proliferation [9,15,21,32,33]. We suggest that the Fig 5.…”

Section: Discussionmentioning

confidence: 52%

Genome-wide analysis of HOXC4 and HOXC6 regulated genes and binding sites in prostate cancer cells

Luo

Farnham

2020

PLoS ONE

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Aberrant expression of HOXC6 and HOXC4 is commonly detected in prostate cancer. The high expression of these transcription factors is associated with aggressive prostate cancer and can predict cancer recurrence after treatment. Thus, HOXC4 and HOXC6 are clinically relevant biomarkers of aggressive prostate cancer. However, the molecular mechanisms by which these HOXC genes contribute to prostate cancer is not yet understood. To begin to address the role of HOXC4 and HOXC6 in prostate cancer, we performed RNA-seq analyses before and after siRNA-mediated knockdown of HOXC4 and/or HOXC6 and also performed ChIP-seq to identify genomic binding sites for both of these transcription factors. Our studies demonstrate that HOXC4 and HOXC6 co-localize with HOXB13, FOXA1 and AR, three transcription factors previously shown to contribute to the development of prostate cancer. We suggest that the aberrantly upregulated HOXC4 and HOXC6 proteins may compete with HOXB13 for binding sites, thus altering the prostate transcriptome. This competition model may be applicable to many different human cancers that display increased expression of a HOX transcription factor.

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“…The observation that a portion of prostate cancer samples overexpresses SPINK1, a trypsin inhibitor that protects the gastrointestinal tract from protease degradation, opened up to the possibility that a gastrointestinal (GI)-lineage specific expression program is activated to promote castration resistance. Accordingly, studies showed that SPINK overexpression is associated with worse prognosis and more rapid progression of resistant tumors [95][96][97][98] and a subclass of CRPC expresses high levels of hepatocyte nuclear factor 4-gamma (HNF4G) and 1-alpha (HNF1A) [99] . These two master transcription factors sustain a GI transcriptional program in prostate cancer, present non-overlapping cistrome with AR, and their exogenous expression leads to resistance to androgen depletion and to enzalutamide in prostate cancer cell lines and xenograft models [99] .…”

Section: Alternative Programs Of Resistancementioning

confidence: 99%

Evolution of the prostate cancer genome towards resistance

Lorenzin¹,

Demichelis²

2019

JTGG

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The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy. CRPCs adapt to androgen receptor (AR) signaling impairment-which follows first-line therapies as androgen deprivation or AR targeting-by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.

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Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance

Cited by 75 publications

References 66 publications

Integrative multi‐omics analysis of intestinal organoid differentiation

Integrative multi‐omics analysis of intestinal organoid differentiation

Genome-wide analysis of HOXC4 and HOXC6 regulated genes and binding sites in prostate cancer cells

Evolution of the prostate cancer genome towards resistance

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