ALDH1A3 correlates with luminal phenotype in prostate cancer

Wang, Shangqian; Liang, Chao; Bao, Meiling; Li, Xiao; Zhang, Lei; Li, Shuang; Qin, Chao; Shao, Pengfei; Li, Jie; Liu, Hua; Wang, Zengjun

doi:10.1177/1010428317703652

Cited by 15 publications

(22 citation statements)

References 28 publications

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“…Our findings suggest that inhibition of BRCA1 and EZH2 expression leads to enrichment of ALDH positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein, whereas cell treatment with a global epigenetic inhibitor DZNeP abrogates this regulation. Of note, a high ALDH1A3 expression is upregulated in prostate tumors as compared to benign prostate hyperplasia tissues, and is associated with lower progression‐free survival in PCa patients that is consistent with a current view that prostate tumors enriched in CSC population have a worse prognosis . Because BRCA1 plays a key role in DNA repair and maintaining chromosome stability, and EZH2 controls genomic stability at replication fork, a reprogramming triggered by BRCA1 and EZH2 inhibition can induce genetically instable CSC‐like populations which can further evolve by acquisition of additional mutations and drive prostate carcinogenesis and heterogeneity.…”

Section: Discussionsupporting

confidence: 82%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem-and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.

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Section: Discussionsupporting

confidence: 82%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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“…ALDH1A3 is androgen responsive in human epithelial LNCaP cells since its expression was 4-fold higher after treatment with dihydrotestosterone (DHT), which indirectly affects both AR regulation and cell differentiation [59] . ALDH1A3 has also been correlated with AR signalling pathway in primary PCa tissue where expression was consistent with luminal layer localisation [65] . Significantly, the study also showed that knockdown of ALDH1A3 led to substantial reductions in proliferation rate and the invasive ability of PC-3 cells.…”

Section: Aldh Expression and Regulation In Prostate Cancermentioning

confidence: 83%

“…In PCa, several ALDH isoforms (1A1, 1A3, 3A1, 3A2, 4A1, 7A1, 9A1 and 18A1) have been found to be overexpressed [15,[60][61][62][63][64][65][66][67][68] , but only a few isoforms appear to play critical roles in PCa. In a recent proteomic study [69] , ALDH1A3 expression was in part controlled via miR-187, as downregulation of this microRNA led to induction of ALDH1A3, while re-introduction decreased ALDH1A3 expression in PC-3, DU145 and LNCAP prostate cancer cells.…”

Section: Aldh Expression and Regulation In Prostate Cancermentioning

confidence: 99%

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Ibrahim¹,

Sadiq²,

Frame³

et al. 2018

JCMT

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The functional role of aldehyde dehydrogenases (ALDHs) in prostate cancer remains an area of some controversy. Many studies have used high ALDH functional activity to isolate putative cancer stem cells with tumour-initiating and propagating properties, while evidence is also emerging about the involvement of specific isoforms in migration, invasiveness and metastasis. Identification of specific ALDH isoforms, which contribute to both drug resistance and aggressiveness of the disease remains a challenge within the complex heterogeneity of prostate cancer. The purpose of this perspective is to dissect functional roles for ALDH in the tumour microenvironment and to evaluate the potential of the ALDH gene family as biomarkers and/or targets for therapeutic intervention. ABSTRACTArticle history:

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“…The level of ALDHs enzymatic activity has been regarded as a cancer stem cell (CSC) marker and seems to correlate with tumor aggressiveness [4] which has been investigated in pancreatic cancer [5], ovarian cancer [6], breast cancer [7], and high-grade glioma [8]. From our previous report [9], we found that ALDH1A3 highly expressed in the human prostate, specially in the luminal compartment. In the primary prostate cancer, the expression of this gene correlated with AR pathway and luminal markers.…”

Section: Introductionmentioning

confidence: 95%

ALDH1A3 serves as a predictor for castration resistance in prostate cancer patients

et al. 2020

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Background: Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells. Methods: We retrospectively reviewed our patients with advanced disease on adjuvant hormonal therapy after prostatectomy. Time to castration resistance stage was documented. And Immunohistochemistry analysis for ALDH1A3 was performed for those patient samples on tissue microarray. Bioinformatics anslysis was used for RNA sequencing data of both primary prostate cancer and metastatic castration resistance prostate cancer (mCRPC) from online datasets. Crispr-Cas9 was used to knock out ALDH1A3 in prostate cancer luminal cells, and morphologic analysis as well as the Gene Set Enrichment Analysis (GSEA) were facilitated to discover the mechanisms of the resistance phenotype. Results: We found that the patients with ALDH1A3 low expression had shorter time to progression to castration resistance compared with those of higher expression group on adjuvant hormonal therapy after radical prostatectomy. The ALDH1A3 knockout cells gradually acquired resistance to androgen deprivation therapy, a few cells have been found in knockout group showing as that the spindle-like luminal cells in charcoal stripped medium. Furthermore, PI3K pathway activation has been confirmed by Western blot. The PI3K pathway inhibitor BEZ235 has been demonstrated that the acquired ADT resistance by ALDH1A3 down regulation could be rescued by PI3K pathway inhibitor. Conclusion: These results suggested a novel function for ALDH1A3 in development of mCRPC, and indicated PI3K pathway inhibitor has the potential in the treatment of a subgroup of mCRPC patients.

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ALDH1A3 correlates with luminal phenotype in prostate cancer

Cited by 15 publications

References 28 publications

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Expression and regulation of aldehyde dehydrogenases in prostate cancer

ALDH1A3 serves as a predictor for castration resistance in prostate cancer patients

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