Antagonistic action of a synthetic androgen ligand mediated by chromatin remodeling in a human prostate cancer cell line

Sawada, Takahiro; Kanemoto, Yoshitsugu; Amano, Rei; Hayakawa, Akira; Kurokawa, Tomohiro; Mori, Jinichi; Kato, Shigeaki

doi:10.1016/j.bbrc.2022.04.109

Cited by 6 publications

(12 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this purpose, chromatin accessibility was assessed by an ATAC-seq approach in ligand-treated HaCaT cells endogenously expressing VDR in comparison with the effect of Bic in LNCaP cells by calculating chromatin openness in the whole genome. Consistent with our previous report [33], Bic treatment for 5 hours was potent to remodel chromatin (S2A and S2C…”

Section: No Effect Of 1α25(oh) 2 D 3 or Dlam-2b On Chromatin Opening ...supporting

confidence: 93%

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells

Iwaki,

Kanemoto,

Sawada

et al. 2023

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Vitamin D (VD) exerts a wide variety of biological functions including calcemic activity. VD nutritional status is closely associated with the onset and development of chronic diseases. To develop a VD analog with the desired VD activity but without calcemic activity, we screened synthetic VDR antagonists. We identified 1α,25-dihydroxyvitamin D3-26-23-lactams (DLAM)-2a-d (DLAM-2s) as nuclear vitamin D receptor (VDR) ligands in a competitive VDR binding assay for 1α,25(OH)2 vitamin D3 (1α,25(OH)2D3), and DLAM-2s showed an antagonistic effect on 1α,25(OH)2 D3-induced cell differentiation in HL60 cells. In a luciferase reporter assay in which human VDR was exogenously expressed in cultured COS-1 cells, DLAM-2s acted as transcriptional antagonists. Consistently, DLAM-2s had an antagonistic effect on the 1α,25(OH)2D3-induced expression of a known VD target gene [Cytochrome P450 24A1 (CYP24A1)], and VDR bound DLAM-2s was recruited to an endogenous VD response element in chromatin in human keratinocytes (HaCaT cells) endogenously expressing VDR. In an ATAC-seq assay, the effects of 1α,25(OH)2 D3 and DLAM-2b on chromatin reorganization were undetectable in HaCaT cells, while the effect of an androgen receptor (AR) antagonist (bicalutamide) was confirmed in prostate cancer cells (LNCaP) expressing endogenous AR. However, whole genome analysis using RNA-seq and ATAC (Assay for Transposase Accessible Chromatin)-seq revealed differential gene expression profiles regulated by DLAM-2b versus 1α,25(OH)2D3. The upregulated and downregulated genes only partially overlapped between cells treated with 1α,25(OH)2D3 and those treated with DLAM-2b. Thus, the present findings illustrate a novel VDR ligand with gene regulatory activity differing from that of 1α,25(OH)2D3.

show abstract

Section: No Effect Of 1α25(oh) 2 D 3 or Dlam-2b On Chromatin Opening ...supporting

confidence: 93%

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells

Iwaki,

Kanemoto,

Sawada

et al. 2023

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…We hypothesized that dual p42-MAPK and Rheb knockdown would boost the toxic effect of DTX, a taxane drug that inhibits microtubule depolymerization, which is one of the first-line antitumoral drugs used in prostate cancer treatment. Their simultaneous knockdown significantly boosted the maximum toxic effect of DTX in human LnCaP cells, which are considered a good model for the early stages of androgen-dependent prostate cancer [52]. In contrast, no such effect was observed in human PC3 cells, a model for more advanced castration-resistant prostate cancer [53].…”

Section: Discussionmentioning

confidence: 99%

A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells

et al. 2022

View full text Add to dashboard Cite

Synthetic double-stranded small interfering RNAs (siRNAs) mimic interference RNAs (RNAi) and can bind target mRNAs with a high degree of specificity, leading to selective knockdown of the proteins they encode. However, siRNAs are very labile and must be both protected and transported by nanoparticles to be efficiently delivered into cells. In this work, we used a Janus-type polycationic amphiphilic β-cyclodextrin derivative to efficiently transfect siRNAs targeting mRNAs encoding mitogen-activated protein kinase (p42-MAPK) or Ras homolog enriched in brain (Rheb) into different cancer cell lines as well as astrocytes. We took advantage of this high transfection efficiency to simultaneously knock down p42-MAPK and Rheb to boost docetaxel (DTX)-mediated toxicity in two human prostate cancer cell lines (LNCaP and PC3). We found that double knockdown of p42-MAPK and Rheb increased DTX-toxicity in LNCaP but not in PC3 cells. However, we also observed the same effect when scramble siRNA was used, therefore pointing to an off-target effect. Indeed, we found that the siRNA we used in this work induced toll-like receptor 3 activation, leading to β-interferon production and caspase activation. We believe that this mechanism could be very useful as a general strategy to elicit an immune response against prostate cancer cells.

show abstract

“…Similar to other types of cancer, epigenetic regulators are involved in prostate cancer, and their malfunction has been well-documented ( Gao and Alumkal, 2010 ; Thompson et al, 2022 ). Recently, the effect of a canonical AR antagonist (bicalutamide: Bic) in chromatin remodeling and expression profile in a human prostate cancer cell line (LNCaP cells) was examined ( Sawada et al, 2022 ). ATAC-seq analysis showed that Bic-induced rearrangement pattern of the chromatin array was different from DHT-induced rearrangement ( Figure 3 ), indicating that Bic is also effective in remodeling the chromatin array.…”

Section: Introductionmentioning

confidence: 99%

“…ATAC-seq analysis showed that Bic-induced rearrangement pattern of the chromatin array was different from DHT-induced rearrangement ( Figure 3 ), indicating that Bic is also effective in remodeling the chromatin array. Additionally, Bic acted as a transcriptional antagonist for AR function ( Sawada et al, 2022 ). Although it is unclear if other AR antagonists are capable of remodeling the chromatin array, clinical studies have shown that these treatments modulate the chromatin landscape.…”

Section: Introductionmentioning

confidence: 99%

The epigenetic function of androgen receptor in prostate cancer progression

Sawada

Kanemoto

Kurokawa

et al. 2023

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Androgen and androgen deprivation (castration) therapies, including androgen receptor antagonists, are clinically used to treat patients with prostate cancer. However, most hormone-dependent prostate cancer patients progress into a malignant state with loss of hormone-dependency, known as castration (drug)-resistant prostate cancer (CRPC), after prolong androgen-based treatments. Even in the CRPC state with irreversible malignancy, androgen receptor (AR) expression is detectable. An epigenetic transition to CRPC induced by the action of AR-mediated androgen could be speculated in the patients with prostate cancer. Androgen receptors belongs to the nuclear receptor superfamily with 48 members in humans, and acts as a ligand-dependent transcriptional factor, leading to local chromatin reorganization for ligand-dependent gene regulation. In this review, we discussed the transcriptional/epigenetic regulatory functions of AR, with emphasis on the clinical applications of AR ligands, AR protein co-regulators, and AR RNA coregulator (enhancer RNA), especially in chromatin reorganization, in patients with prostate cancer.

show abstract

Antagonistic action of a synthetic androgen ligand mediated by chromatin remodeling in a human prostate cancer cell line

Cited by 6 publications

References 35 publications

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells

A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells

The epigenetic function of androgen receptor in prostate cancer progression

Contact Info

Product

Resources

About