Sp1 and the ‘hallmarks of cancer’

Beishline, Kate; Azizkhan‐Clifford, Jane

doi:10.1111/febs.13148

Cited by 457 publications

(436 citation statements)

References 372 publications

(324 reference statements)

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“…Five genes were down-regulated by enzalutamide treatment, including FOS and JUN (components of the early-response transcription factor AP-1) and the transcription factor SP-1. Both AP-1 and SP-1 are critical for the regulation of genes involved in proliferative signalling, replicative immortality, cell metabolism, as well as cell invasion and metastasis (Vesely et al 2009, Beishline & Azizkhan Clifford 2015. Both FOS and JUN were further validated by RT-PCR as being significantly down-regulated by enzalutamide, specifically in AR-positive cells.…”

Section: Discussionmentioning

confidence: 97%

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC 50 values for the secondgeneration anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.

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Section: Discussionmentioning

confidence: 97%

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

Endocrine-Related Cancer

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“…In cancer growth and metastasis, Sp1 influences a variety of cancer cell types through the regulation of oncogenes, tumor suppressor genes, cell cycle regulators, growth related signal transduction pathways, angiogenic factors and apoptosis (5,6). Sp1 is expressed at high levels in many cancers (7) and is closely associated with EMT (8,9).…”

Section: Introductionmentioning

confidence: 99%

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

Shan

Hu³

et al. 2016

International Journal of Oncology

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Abstract. Sp1 plays critical roles in epithelial-mesenchymal transition (EMT) of certain cancer. However, few studies have indicated whether Sp1 is involved in the EMT of gastric cancer, and whether abnormal expression of Sp1 in gastric cancer EMT is regulated in a post-transcriptional manner, and the involvement of miRNAs in this regulation. In this study, we selected 20 cases of gastric cancers, their liver metastases and para-carcinoma tissues to examine the levels of Sp1 protein and mRNA by immunohistochemistry and fluorescent PCR, which showed that Sp1 was increased in gastric cancers and their metastases compared with adjacent tissues, but there was no difference in Sp1 mRNA between these three groups, suggesting changes in Sp1 may be attributed to inactivation of post-transcriptional regulation. We verified by a luciferase reporter system that miRNA-223 binds to 3'-UTR of Sp1 gene and inhibits its translation, in agreement with negative correlation between miRNA-223 and Sp1 protein levels in gastric cancer cells. By employing TGF-β1 to induce MGC-803, BGC-823 and SGC-7901, we successfully built cellular EMT model. Then, we overexpressed miRNA-223 in the model by using a lentiviral system, which diminished EMT indicators and suppressed proliferation and invasion ability, and induced apoptosis. Finally, we verified the specificity of the regulation pathway miRNA-223/Sp1/EMT. These findings suggest that low expression of miRNA-223 in gastric cancer cells is an important cause for EMT. miRNA-223 specifically regulates the EMT process of gastric cancer cells through its target gene Sp1. Overexpression of miRNA-223 in these cells inhibits EMT via the miRNA-223/Sp1/EMT pathway.

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“…Specificity protein 1 (SP1) regulates many biological functions, including cell growth, differentiation, and survival, as well as tumor progression and metastasis (Banerjee et al ., 2013; Beishline and Azizkhan‐Clifford, 2015; Deniaud et al ., 2009; Hedrick et al ., 2016; Kanai et al ., 2006). Multiple studies have underscored the importance of SP1 in malignant tissues (Banerjee et al ., 2013; Deniaud et al ., 2009; Kanai et al ., 2006).…”

Section: Introductionmentioning

confidence: 99%

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

et al. 2018

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Chemoresistance is a major therapeutic challenge that plays a role in the poor statistical outcomes in pancreatic cancer. Unfolded protein response (UPR) is one of the homeostasis mechanisms in cancer cells that have been correlated with chemoresistance in a number of cancers including pancreatic cancer. In this study, we show that modulating glucose regulatory protein 78 (GRP78), the master regulator of the UPR, can have a profound effect on multiple pathways that mediate chemoresistance. Our study showed for the first time that silencing GRP78 can diminish efflux activity of ATP‐binding cassette (ABC) transporters, and it can decrease the antioxidant response resulting in an accumulation of reactive oxygen species (ROS). We also show that these effects can be mediated by the activity of specificity protein 1 (SP1), a transcription factor overexpressed in pancreatic cancer. Thus, inhibition of SP1 negatively affects the UPR, deregulates the antioxidant response of NRF2, as well as ABC transporter activity by inhibiting GRP78‐mediated ER homeostasis. Sp1 and NRF2 have been classified as nononcogene addiction genes and thus are imperative to understanding the molecular mechanism of resistance. These finding have huge clinical relevance as both Sp1 and GRP78 are overexpressed in pancreatic cancer patients and increased expression of these proteins is indicative of poor prognosis. Understanding how these proteins may regulate chemoresistance phenotype of this aggressive cancer may pave the way for development of efficacious therapy for this devastating disease.

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Sp1 and the ‘hallmarks of cancer’

Cited by 457 publications

References 372 publications

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

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