Single-cell analysis reveals androgen receptor regulates the ER-to-Golgi trafficking pathway with CREB3L2 to drive prostate cancer progression

Hu, Lingling; Chen, Xin; Narwade, Nitin; Lim, Michelle Gek Liang; Chen, Zikai; Tennakoon, Chandana; Guan, Peiyong; Chan, Un In; Zhao, Zhenqun; Deng, Mokan; Xu, Xiaoling; Sung, Wing‐Kin; Cheung, Edwin

doi:10.1038/s41388-021-02026-7

Cited by 11 publications

(10 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of VCaP cells treated with the third-generation antiandrogen enzalutamide (gene set GSE62473) revealed an upregulation of DNA replication, DNA repair, and cell cycle. Furthermore, ER-Golgi transport processes seemed downregulated, in line with a recent report of others ( Figure 4 A,B) [ 53 ]. Treatment of VCaP cells with bicalutamide had nearly identical consequences to treatment with enzalutamide ( Supplementary Figure S2 ).…”

Section: Resultssupporting

confidence: 91%

Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer—Experimental and Computational Analyses

Basílio

Hochreiter

Hoesel

et al. 2022

Cancers

View full text Add to dashboard Cite

Prostate cancer is very frequent and is, in many countries, the third-leading cause of cancer related death in men. While early diagnosis and treatment by surgical removal is often curative, metastasizing prostate cancer has a very bad prognosis. Based on the androgen-dependence of prostate epithelial cells, the standard treatment is blockade of the androgen receptor (AR). However, nearly all patients suffer from a tumor relapse as the metastasizing cells become AR-independent. In our study we show a counter-regulatory link between AR and NF-κB both in human cells and in mouse models of prostate cancer, implying that inhibition of AR signaling results in induction of NF-κB-dependent inflammatory pathways, which may even foster the survival of metastasizing cells. This could be shown by reporter gene assays, DNA-binding measurements, and immune-fluorescence microscopy, and furthermore by a whole set of computational methods using a variety of datasets. Interestingly, loss of PTEN, a frequent genetic alteration in prostate cancer, also causes an upregulation of NF-κB and inflammatory activity. Finally, we present a mathematical model of a dynamic network between AR, NF-κB/IκB, PI3K/PTEN, and the oncogene c-Myc, which indicates that AR blockade may upregulate c-Myc together with NF-κB, and that combined anti-AR/anti-NF-κB and anti-PI3K treatment might be beneficial.

show abstract

Section: Resultssupporting

confidence: 91%

Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer—Experimental and Computational Analyses

Basílio

Hochreiter

Hoesel

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Such processes have received little attention in PC. In VCaP and LNCaP cells, androgen treatment promotes Endoplasmic-Reticulum-to-Golgi vesicle trafficking by increasing transcription of protein transport genes (including CREB3L2 , a transcription factor that co-localizes with AR) [ 40 ]. Additionally, CRPC cells release paracrine-acting factors that stimulate bone-derived mesenchymal stem cells and stromal cells of fibroblast lineage [ 41 , 42 ], suggesting that secretion may be advantageous for CRPC progression and tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The kinesin KIF20A promotes progression to castration-resistant prostate cancer through autocrine activation of the androgen receptor

Copello

Burnstein

2022

Oncogene

View full text Add to dashboard Cite

Prostate cancer that recurs following androgen-deprivation therapy is termed castration-resistant, which is incurable and is marked by reactivation of androgen receptor (AR) signaling. KIF20A, a kinesin with unique structural features, is overexpressed in human castration-resistant prostate cancer (CRPC) compared to androgen-dependent PC and benign tissue. KIF20A has well-described roles in mitotic processes, but it has a less characterized function in vesicle fission and trafficking within Golgi-driven secretory pathways. Stable expression of KIF20A in androgen-dependent PC cells promoted progression to CRPC through the activation of AR signaling in vitro and in vivo . KIF20A expression resulted in the secretion of autocrine factors in the conditioned media that activated AR and caused castration-resistant proliferation of naïve androgen-dependent cells. Pharmacologic disruption of vesicle biogenesis blocked KIF20A-driven castration-resistant proliferation of androgen-dependent PC. KIF20A depletion or treatment with the KIF20A-specific inhibitor, paprotrain, reduced CRPC . These data are the first to establish KIF20A as a driver of CRPC progression through AR activation and as a promising therapeutic target against CRPC.

show abstract

“…While both CREB3L1 and 2 are transcriptionally induced in stimulated EnSC, only CREB3L1 increases also at the protein level, suggesting that different processing mechanisms may apply to either of the two TF. Androgen receptor activates CREB3L2, increasing protein trafficking in prostate cancers ( Hu et al, 2021 ), but the biochemical details remain to be elucidated. It is tempting to speculate that similar mechanisms are shared by progesterone receptor, which will be a topic for further studies.…”

Section: Discussionmentioning

confidence: 99%

CREB3L1 and CREB3L2 control Golgi remodelling during decidualization of endometrial stromal cells

Pittari

Torre

Borini

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Upon progesterone stimulation, Endometrial Stromal Cells (EnSCs) undergo a differentiation program into secretory cells (decidualization) to release in abundance factors crucial for embryo implantation. We previously demonstrated that decidualization requires massive reshaping of the secretory pathway and, in particular, of the Golgi complex. To decipher the underlying mechanisms, we performed a time-course transcriptomic analysis of in vitro decidualizing EnSC. Pathway analysis shows that Gene Ontology terms associated with vesicular trafficking and early secretory pathway compartments are the most represented among those enriched for upregulated genes. Among these, we identified a cluster of co-regulated genes that share CREB3L1 and CREB3L2 binding elements in their promoter regions. Indeed, both CREB3L1 and CREB3L2 transcription factors are up-regulated during decidualization. Simultaneous downregulation of CREB3L1 and CREB3L2 impairs Golgi enlargement, and causes dramatic changes in decidualizing EnSC, including Golgi fragmentation, collagen accumulation in dilated Endoplasmic Reticulum cisternae, and overall decreased protein secretion. Thus, both CREB3L1 and CREB3L2 are required for Golgi reshaping and efficient protein secretion, and, as such, for successful decidualization.

show abstract

Single-cell analysis reveals androgen receptor regulates the ER-to-Golgi trafficking pathway with CREB3L2 to drive prostate cancer progression

Cited by 11 publications

References 93 publications

Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer—Experimental and Computational Analyses

Antagonistic Functions of Androgen Receptor and NF-κB in Prostate Cancer—Experimental and Computational Analyses

The kinesin KIF20A promotes progression to castration-resistant prostate cancer through autocrine activation of the androgen receptor

CREB3L1 and CREB3L2 control Golgi remodelling during decidualization of endometrial stromal cells

Contact Info

Product

Resources

About