The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer

Quan, Yongjun; Zhang, Xiaodong; Butler, Wayne M.; Du, Zhaohui; Wang, Mingdong; Liu, Yuexin; Hao, Ping

doi:10.7150/ijbs.63300

Cited by 18 publications

(19 citation statements)

References 79 publications

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“…A subsequent decrease in PCa cell proliferation and migration was also observed in response to NDRG1 overexpression. This finding supports earlier studies demonstrating the potent ability of NDRG1 to inhibit invasion and metastatic progression of PCa in vitro and in vivo ( 19 , 23 , 27 , 29 , 33 , 103 , 104 ). As EGF-mediated activation of the abovementioned pathways plays a central role in androgen-independent AR activation ( 116 , 117 , 118 ), this suggests that NDRG1 may suppress the development of androgen resistance in PCa.…”

Section: Discussionsupporting

confidence: 92%

“…Comparing the endogenous expression of NDRG1 between the three different cell types used (androgen-dependent LNCaP cells and androgen-independent 22Rv1 and C4-2B cells), all had similar endogenous NDRG1 levels and also expressed the AR. Notably, earlier studies have shown that the AR directly regulates NDRG1 transcription by binding to the ARE in the NDRG1 promoter ( 101 , 102 ), with this interaction being mediated by other cofactors, such as c-JUN or MLL5, to promote either positive or negative regulation of NDRG1 ( 103 , 104 ). However, our current findings establish for the first time that NDRG1 interacts with and influences the activation and accumulation of the AR.…”

Section: Discussionmentioning

confidence: 99%

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The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer

Lim

Geleta

Maleki

et al. 2021

Journal of Biological Chemistry

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N-myc-downregulated gene 1 (NDRG1) has potent anticancer effects and inhibits cell growth, survival, metastasis, and angiogenesis. Previous studies suggested that NDRG1 is linked to the androgen signaling network, but this mechanistic relationship is unclear. Considering the crucial role of the androgen receptor (AR) in prostate cancer (PCa) progression, here we examined for the first time the effect of NDRG1 on AR expression, activation, and downstream signaling in LNCaP, 22Rv1, and C4-2B PCa cell types. We demonstrate that NDRG1 effectively promotes interaction of AR with the chaperone HSP90, which in turn stabilizes the AR while decreasing its androgen-mediated activation. The expression of NDRG1 suppressed: (1) AR activation, as measured by p-AR Ser213 and p-AR Ser81 ; (2) expression of a major AR transcriptional target, prostate-specific antigen (PSA); and (3) AR transcriptional activity, probably via inhibiting the c-Jun-AR interaction by reducing c-Jun phosphorylation (p-c-Jun Ser63 ). NDRG1 was also demonstrated to inhibit multiple key molecules involved in androgen-dependent and -independent signaling (namely EGFR, HER2, HER3, PI3K, STAT3, and NF-κB), which promote the development of castration-resistant prostate cancer. We also identified the cysteine-rich secretory protein/antigen 5/pathogenesis related-1 (CAP) domain of NDRG1 as vital for inhibition of AR activity. Examining NDRG1 and p-NDRG1 in PCa patient specimens revealed a significant negative correlation between NDRG1 and PSA levels in prostatectomy patients that went on to develop metastasis. These results highlight a vital role for NDRG1 in androgen signaling and its potential as a key therapeutic target and biomarker in PCa.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer

Lim

Geleta

Maleki

et al. 2021

Journal of Biological Chemistry

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“…It has been reported that epigenetic reprogramming is key for PCa progression [ 29 , 30 ] and that inhibition of the epigenetic regulator EZH2 might effectively overcome ADT resistance [ 2 ]. Our previous study found that epigenetically activating AR/NDRG1 signaling through histone methylation and DNA methylation significantly suppresses CRPC progression [ 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…qPCR analysis was performed as previously described by our group [ 20 , 21 ]. Total RNA was isolated using TRIzol™ reagent (Invitrogen), and complementary DNA (cDNA) was synthesized through One-Step gDNA Removal and cDNA Synthesis SuperMix (TransGen Biotech, Beijing, China).…”

Section: Methodsmentioning

confidence: 99%

Construction of a risk prediction model using m6A RNA methylation regulators in prostate cancer: comprehensive bioinformatic analysis and histological validation

2022

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Background Epigenetic reprogramming reportedly has a crucial role in prostate cancer (PCa) progression. RNA modification is a hot topic in epigenetics, and N6-methyladenosine (m6A) accounts for approximately 60% of RNA chemical modifications. The aim of this study was to evaluate the m6A modification patterns in PCa patients and construct a risk prediction model using m6A RNA regulators. Materials and methods Analyses were based on the levels of 25 m6A regulators in The Cancer Genome Atlas (TCGA). Differentially expressed gene (DEG) and survival analyses were performed according to TCGA-PRAD clinicopathologic and follow-up information. To detect the influences of m6A regulators and their DEGs, consensus clustering analysis was performed, and tumor mutational burden (TMB) estimation and tumor microenvironment (TME) cell infiltration were assessed. mRNA levels of representative genes were verified using clinical PCa data. Results Diverse expression patterns of m6A regulators between tumor and normal (TN) tissues were detected regarding Gleason score (GS), pathological T stage (pT), TP53 mutation, and survival comparisons, with HNRNPA2B1 and IGFBP3 being intersecting genes. HNRNPA2B1 was upregulated in advanced stages (GS > 7, pT3, HR > 1, and TP53 mutation), as verified using clinical PCa tissue. Three distinct m6A modification patterns were identified through consensus clustering analysis, but no significant difference was found among these groups in recurrence-free survival (RFS) analysis. Six DEGs of m6A clusters (m6Aclusters) were screened through univariate Cox regression analysis. MMAB and PAIAP2 were intersecting genes for the five clinical factors. MMAB, which was upregulated in PCa compared with TN, was verified using clinical PCa samples. Three distinct subgroups were established according to the 6 DEGs. Cluster A involved the most advanced stages and had the poorest RFS. The m6A score (m6Ascore) was calculated based on the 6 genes, and the low m6Ascore group showed poor RFS with a negative association with infiltration for 16 of 23 immune-related cells. Conclusion We screened DEGs of m6Aclusters and identified 6 genes (BAIAP2, TEX264, MMAB, JAGN1, TIMM8AP1, and IMP3), with which we constructed a highly predictive model with prognostic value by dividing TCGA-PRAD into three distinct subgroups and performing m6Ascore analysis. This study helps to elucidate the integral effects of m6A modification patterns on PCa progression.

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“…Quantitative real-time PCR (qPCR) analysis qPCR analysis was performed as previously described by us [20,21]. Total RNA was isolated using TRIzol™ reagent (Invitrogen) and Complementary DNA (cDNA) was synthesized through One-Step gDNA Removal and cDNA Synthesis SuperMix (TransGen Biotech, Beijing, China).…”

Section: Clinical Pca Samplesmentioning

confidence: 99%

Construction of risk prediction model using m6A RNA methylation regulators in prostate cancer: comprehensive bioinformatic analysis and histological validation

Quan¹,

Zhang²,

Ping³

2021

Preprint

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Background Epigenetic reprogramming reportedly has a crucial role in prostate cancer (PCa) progression. RNA modification is a hot topic in epigenetics, and N6-methyladenosine (m6A) accounts for approximately 60% of RNA chemical modifications. The aim of this study was to construct risk prediction model using m6A RNA regulators in PCa. Materials and methods Analyses were based on levels of 25 m6A regulators in The Cancer Genome Atlas (TCGA). Differential expression gene (DEG) and survival analyses were performed according to TCGA-PRAD clinicopathologic and follow-up information. To detect the influence of m6A regulators and their DEGs, consensus clustering analysis was performed, and tumor mutational burden (TMB) estimation and tumor microenvironment (TME) cell infiltration were assessed. mRNA levels of representative genes were verified using clinical PCa data. Results Diverse expression patterns of m6A regulators between tumor and normal (TN) were detected regarding Gleason score (GS), pathological T stage (pT), TP53 mutation, and survival comparisons, with HNRNPA2B1 and IGFBP3 being intersecting genes. HNRNPA2B1 was upregulated in advanced stages (GS > 7, pT3, HR >1, and TP53 mutation), as verified using clinical PCa tissue. Three distinct m6A modification patterns were identified through consensus clustering analysis but no significant difference was found among these groups in recurrence -free survival (RFS) analysis. Six DEGs of m6A clusters were screened through univariate Cox regression analysis. MMAB and PAIAP2 were intersecting genes for the five clinical factors. MMAB, which was upregulated in PCa compared with TN, was verified using clinical PCa samples. Three distinct subgroups were established according to the 6 DEGs. Cluster A involved the most advanced stages and had the poorest RFS. The m6A score (m6Ascore) was calculated based on the 6 genes, and the low m6Ascore group showed poor RFS with a negative association with infiltration of 16 of 23 immune-related cells. Conclusion We screened DEGs of m6A clusters and identified 6 genes (BAIAP2, TEX264, MMAB, JAGN1, TIMM8AP1, and IMP3), with which constructed a high predictive model with prognostic value by dividing TCGA-PRAD into three distinct subgroups and performing m6A core analysis. This study helps in elucidating the integral effects of m6A signaling on PCa progression.

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The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer

Cited by 18 publications

References 79 publications

The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer

The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer

Construction of a risk prediction model using m6A RNA methylation regulators in prostate cancer: comprehensive bioinformatic analysis and histological validation

Construction of risk prediction model using m6A RNA methylation regulators in prostate cancer: comprehensive bioinformatic analysis and histological validation

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