PBX3 is a putative biomarker of aggressive prostate cancer

Ramberg, Håkon; Grytli, Helene Hartvedt; Nygård, Ståle; Wang, Wanzhong; Ögren, Olov; Zhao, Sen; Løvf, Marthe; Katz, Betina; Skotheim, Rolf Inge; Bjartell, Anders; Eri, Lars M.; Berge, Viktor; Svindland, Aud; Taskén, Kristin Austlid

doi:10.1002/ijc.30220

Cited by 33 publications

(40 citation statements)

References 31 publications

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“…22,23 TargetScan, miRDB, and TargetMiner revealed that genes other than LIN28B, such as CDC34, PBX3, and FZD3, were predicted as candidate miR-4500 targets. PBX3 is overexpressed in gastric cancer and prostate cancer 24,25 and promotes CRC migration by regulating the MAPK/ERK pathway. 26 CDC34 is highly expressed in multiple myeloma (MM) and associated with the growth and survival of MM cells.…”

Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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This study aimed to understand the exact function and potential mechanism of miR-4500 in colorectal cancer (CRC). In this study, the expression of miR-4500 was decreased in both CRC cells and tissues, and downregulated miR-4500 indicated advanced tumor stage and poor survival. By bisulfite sequencing analysis, we found that the CpG island in the promoter region of miR-4500 was hypermethylated in CRC cells and tissues compared with normal control cells and non-tumor tissues, respectively. Functionally, gain-and loss-of-function analyses indicated the tumor suppressor role of miR-4500: it suppressed cell proliferation, cell cycle progression, migration, and invasion. Predictive algorithms and experimental analyses identified HMGA2 as a direct target of miR-4500. Reintroducing HMGA2 impaired the inhibitory effects of miR-4500 on cell growth and motility. Clinically, higher HMGA2 protein expression in CRC tissues was associated with advanced tumor stage and poor survival. An inverse correlation was found between miR-4500 levels and HMGA2 protein expression. Taken together, this study provides the first evidence that miR-4500 functions as a novel tumor suppressor in the miR-4500/HMGA2 axis in colorectal carcinogenesis, and restoring miR-4500 expression might represent a promising therapeutic strategy for CRC.Abbreviations: CRC, Colorectal cancer; HMGA2, high mobility group AT-hook 2; 5-aza, 5-aza-2 0 -deoxycytidine

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Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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“…Because PBX1 was highly expressed in PCa tissues and cell lines, and its homolog PBX3 is a putative progressive biomarker in PCa (7), we wondered whether PBX1 was important for PCa cell proliferation and survival. To this end, we used DU145 that lacks PBX1 and PC3 that expresses PBX1 for next studies.…”

Section: Pbx1 Promotes Pca Cell Proliferationmentioning

confidence: 99%

“…In gastric carcinomas (5) and nonsmall cell lung cancers (6), PBX1 promotes epithelial to mesenchymal transition that is associated cro ARTICLE with chemoresistance. Although there are less studies on PBX1 in PCa, a recent study revealed that PBX3, a homolog of PBX1, is a putative biomarker of aggressive PCa (7). There are two PBX1 transcripts: PBX1a and PBX1b, between which the only difference is that PBX1b lacks the 7th exon (8), but their biological functions remain very similar as a transcription factor.…”

mentioning

confidence: 99%

Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis

Liu

Lin

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan WangChemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immune histochemical, chemistry, and precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin. We observed that genetic PBX1 knockdown abrogates this resistance, and further experiments revealed that PBX1 stability was modulated by the ubiquitin-proteasomal pathway. To directly probe the impact of this pathway on PBX1 activity, we screened for PBX1-specific deubiquitinases (Dubs) and found that ubiquitin-specific peptidase 9 X-linked (USP9x) interacted with and stabilized the PBX1 protein by attenuating its Lys-48 -linked polyubiquitination. Moreover, the USP9x inhibitor WP1130 markedly induced PBX1 degradation and promoted PCa cell apoptosis. The results in this study indicate that PBX1 confers to PCa chemoresistance and identify USP9x as a Dub of PBX1. We concluded that targeting the USP9x/ PBX1 axis could be a potential therapeutic strategy for managing advanced prostate cancer.Prostate cancer (PCa) 4 is a malignant disease developed in the prostate, a gland in the male reproductive system. The epidemiological studies reveal that PCa is one of the most common cancers in men and one of the leading causes of cancer-related deaths worldwide (1). Several treatment modalities have been developed against prostate cancers, including androgen-deprivation therapy, localized radiotherapy and chemotherapy. Currently, androgendeprivation therapy is the standard frontline therapy for advanced PCa patients; nevertheless, most patients will eventually develop resistance and these castration-resistant PCa patients rely on chemotherapy. Unfortunately, this regimen only prolongs modest survival of PCa patients, of which many acquire chemoresistance and eventually evolve to a fatal clinical outcome (1). It is widely believed that molecular and genetic events are key players in the resistance but they are not well defined.Pre-B cell leukemia homeobox-1 (PBX1), a member of the TALE (three-amino acid loop extension) family of atypical homeodomain proteins, is cloned from pre-B cell leukemia (2), our recent study demonstrated that it up-regulates the transcription of ring finger protein 6 and contributes to leukemia chemoresistance (3). However, more and more evidence shows that PBX1 is dysregulated and contributes to proliferation, survival, metastasis, and chemoresistance in various solid tumors, including breast, lung, gastric, and ovarian cancers. For example, high expression of PBX1 drives breast cancer proliferation and metastasis by regulating the estrogen receptor transcriptional re...

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“…It belongs to the TALE/PBXHOX family with a highly conserved homologous domain, which binds to the sequence 5′-ATCAATCAA-3′ by interacting with other homologous proteins (such asMEIS1 and HOXA9), resulting in transcription activation or target gene silencing [7,9,10]. Many reports demonstrated that aberrant expression of PBX3 was closely correlated with survival and tumor growth in patients with gastric and colorectal cancer [14][15][16]. Perturbing the PBX3 interaction with HOX or knockdown PBX3 induced apoptosis and inhibited epithelial-to-mesenchymal transition of tumor cells [9,10].…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of PBX3 induces epithelial-mesenchymal transition and promotes invasion and metastasis of gastric, and colorectal cancer cells [13][14][15]. Moreover, elevated expression of PBX3 is associated with indolent progression to castration-resistant prostate cancer [16,17]. Targeting HOXA9/ PBX3 interaction has been suggested as a new therapeutic strategy to treat leukemia, gastrointestinal cancer, and nonsmall cell lung cancer [5,18,19].…”

Section: Introductionmentioning

confidence: 99%

PBX3 Promotes Tumor Growth and Angiogenesis via Activation of AT1R/VEGFR2 Pathway in Papillary Thyroid Carcinoma

Chen

Zhang

et al. 2020

BioMed Research International

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PBX3 (Pre-B-cell leukemia homeobox 3) had been considered to be a multifunctional oncogene which involved in tumor growth, invasion, and metastasis in leukemia and some solid tumors. However, the contribution of PBX3 to papillary thyroid carcinoma (PTC) remains unclear. In this study, we found that PBX3 expression was significantly upregulated in PTC tissues compared to adjacent normal tissues, and high levels of PBX3 were correlated with tumor size, lymphatic metastasis, TMN stage, and poor prognosis of PTC patients. Overexpression of PBX3 in PTC cell lines promoted cell proliferation. Consistently, knockdown of PBX3 by shRNA induced cell cycle arrest at G0/G1 phase, and inhibited angiogenesis and tumor growth in vitro and in vivo. Furthermore, PBX3 promoted PTC cell proliferation and angiogenesis through activation of AT1R/VEGFR2 pathway while overexpression of AT1R and treatment with VEGFA reversed PBX3-shRNA-induced decreased phosphorylation of VEGFR2 and its downstream (ERK1/2, AKT and Src). It demonstrated that PBX3 could be used as a potential prognostic biomarker and therapeutic target for PTC.

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PBX3 is a putative biomarker of aggressive prostate cancer

Cited by 33 publications

References 31 publications

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis

PBX3 Promotes Tumor Growth and Angiogenesis via Activation of AT1R/VEGFR2 Pathway in Papillary Thyroid Carcinoma

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