Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis,and the androgen receptor regulates prostate cancer(PCa)progression.It is unclear whether the androgen receptor regulates the recr...Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis,and the androgen receptor regulates prostate cancer(PCa)progression.It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment,even bone metastases,through exosomes.Here,we found that exosomes isolated from PCa cells after knocking down androgen receptor(AR)or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts.In addition,AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase(circ-DHPS)in PCa cells,which can be transported to osteoblasts by exosomes.Circ-DHPS acts as a competitive endogenous RNA(ceRNA)against endogenous miR-214-3p to promote C-C chemokine ligand 5(CCL5)levels in osteoblasts.Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment.Thus,blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.展开更多
Chromodomain-helicase-DNA-binding protein 1(CHD1)deletion is among the most common mutations in prostate cancer(PCa),but its role remains unclear.In this study,RNA sequencing was conducted in PCa cells after clustered...Chromodomain-helicase-DNA-binding protein 1(CHD1)deletion is among the most common mutations in prostate cancer(PCa),but its role remains unclear.In this study,RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat(CRISPR)/CRISPR-associated protein 9(Cas9)-based CHD1 knockout.Gene set enrichment analysis(GSEA)indicated upregulation of hypoxia-related pathways.A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α(HIF1α)expression.Mechanistic investigation revealed that CHD1 deletion upregulated HIF1αby transcriptionally downregulating prolyl hydroxylase domain protein 2(PHD2),a prolyl hydroxylase catalyzing the hydroxylation of HIF1αand thus promoting its degradation by the E3 ligase von Hippel–Lindau tumor suppressor(VHL).Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis,possibly through HIF1αtarget genes.Taken together,these findings indicate that CHD1 deletion enhances HIF1αexpression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.展开更多
基金supported by grant from the National Natural Science Foundation of China(No.82002693 and No.81803022)the Natural Science Foundation of Shaanxi Province(No.2022JQ-903 and No.2020JQ-519).
文摘Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis,and the androgen receptor regulates prostate cancer(PCa)progression.It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment,even bone metastases,through exosomes.Here,we found that exosomes isolated from PCa cells after knocking down androgen receptor(AR)or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts.In addition,AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase(circ-DHPS)in PCa cells,which can be transported to osteoblasts by exosomes.Circ-DHPS acts as a competitive endogenous RNA(ceRNA)against endogenous miR-214-3p to promote C-C chemokine ligand 5(CCL5)levels in osteoblasts.Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment.Thus,blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.
基金This study was supported by grants from the National Natural Science Foundation of China(No.82173292 and No.82002693).
文摘Chromodomain-helicase-DNA-binding protein 1(CHD1)deletion is among the most common mutations in prostate cancer(PCa),but its role remains unclear.In this study,RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat(CRISPR)/CRISPR-associated protein 9(Cas9)-based CHD1 knockout.Gene set enrichment analysis(GSEA)indicated upregulation of hypoxia-related pathways.A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α(HIF1α)expression.Mechanistic investigation revealed that CHD1 deletion upregulated HIF1αby transcriptionally downregulating prolyl hydroxylase domain protein 2(PHD2),a prolyl hydroxylase catalyzing the hydroxylation of HIF1αand thus promoting its degradation by the E3 ligase von Hippel–Lindau tumor suppressor(VHL).Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis,possibly through HIF1αtarget genes.Taken together,these findings indicate that CHD1 deletion enhances HIF1αexpression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.
