Caspase cleavage of transcription factor Sp1 enhances apoptosis

Torabi, Behzad; Flashner, Samuel; Beishline, Kate; Sowash, Aislinn; Donovan, Kelly; Bassett, Garrett; Azizkhan‐Clifford, Jane

doi:10.1007/s10495-017-1437-4

Cited by 25 publications

(20 citation statements)

References 76 publications

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“…Interestingly, previous studies have reported that bortezomib induces the activation of caspase-8 (Liu et al, 2007;Laussmann et al, 2011;Amodio et al, 2012;Bullenkamp et al, 2014;Bat-Erdene et al, 2016) and bortezomib-mediated Sp1 degradation is blocked by FMK-ZEITD (Bat-Erdene et al, 2016). A role for caspase-3-dependent cleavage of Sp1 has also been reported (Torabi et al, 2018). The inhibition of bortezomib-induced effects by FMK-ZEITD is consistent with the observed induction of caspase-8 in MM cells (ANBL-6 and RPMI 8226) ( Fig.…”

Section: Bortezomib Decreases Expression Of Sp Transcription Factors supporting

confidence: 86%

Bortezomib Targets Sp Transcription Factors in Cancer Cells

2018

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Bortezomib alone and in combination with other anticancer agents are extensively used for chemotherapeutic treatment of multiple myeloma (MM) patients and are being developed for treating other cancers. Bortezomib acts through multiple pathways, and in this study with ANBL-6 and RPMI 8226 MM cells we show that bortezomib inhibited growth and induced apoptosis and that this was accompanied by downregulation of specificity protein (Sp) 1, Sp3, and Sp4 transcription factors that are overexpressed in these cells. Similar results were observed in pancreatic and colon cancer cells. The functional importance of this pathway was confirmed by showing that individual knockdown of Sp1, Sp3, and Sp4 in MM cells inhibited cell growth and induced apoptosis, and that this correlates with the results of previous studies in pancreatic, colon, and other cancer cell lines. The mechanism of bortezomib-mediated downregulation of Sp transcription factors in MM was due to the induction of caspase-8 and upstream factors, including Fas-associated death domain. These results demonstrate that an important underlying mechanism of action of bortezomib was due to the activation of caspase-8-dependent downregulation of Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated genes.

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Section: Bortezomib Decreases Expression Of Sp Transcription Factors supporting

confidence: 86%

Bortezomib Targets Sp Transcription Factors in Cancer Cells

2018

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“…pLXSN-Sp1-30N (182 N-terminal peptide sequence) was constructed from pLXSN-Flag-Sp1-HA. pLZS-Sp1-30N (Torabi et al, 2018) and Sp1 point mutants were constructed from pLZS-Flag-Sp1. Sp1-30N was constructed by inserting Sal1 restriction sites adjacent to codon 183 of the Sp1 sequence using PCR and the following primers: Forward (5 0 CCC ACA GTT CCA GAC CGT CGA CGG GCA ACA GCT GCA G 3 0 ) and Reverse (5 0 CTG CAG CTG TTG CCC GTC GAC GGT CTG GAA CTG TGG G 3 0 ).…”

Section: Resource Availabilitymentioning

confidence: 99%

“…Among the many proteins involved in recognition of DSBs is specificity protein 1 (Sp1), which has also been implicated in DSB repair (Beishline et al, 2012;Fletcher et al, 2018;Olofsson et al, 2007). Sp1 is ubiquitously expressed and best known as a transcription factor that regulates genes involved in DNA repair, apoptosis, and cell proliferation (Black et al, 2001;Deniaud et al, 2009;Torabi et al, 2018). Sp1's activity is regulated by (A) U2OS cells were pretreated with 10 mM BrdU for 3 h to label cells in the S phase (blue).…”

Section: Introductionmentioning

confidence: 99%

DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1

et al. 2021

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“…Specific protein 1 (Sp1) is one of the earliest identified transcription factors (Beishline and Azizkhan-Clifford 2015). The abnormal activation of Sp1 could up-regulate the expression of tumor related factors and angiogenic factors, thus providing a good microenvironment for tumor growth, and promoting the proliferation, metastasis and angiogenesis of colon, gastric and pancreatic tumors and regulate apoptosis (Beishline and Azizkhan-Clifford 2015;Liu et al 2018;Torabi et al 2018). Sp1 could interact with the promoter of vascular endothelial growth factor A (VEGFA), and up-regulate its expression, which promotes the proliferation of vascular endothelium, angiogenesis and vascular permeability, thus promoting the growth and metastasis of tumor via binding with VEGF receptor 2 (VEGFR2) (Chen et al 2018;Vizcaino et al 2015).…”

Section: Introductionmentioning

confidence: 99%

ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

Zou

Wen

et al. 2020

Mol Med

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Background Breast cancer (BC) is a common malignant tumor with poor prognosis. Angiogenesis is related to the growth and progression of solid tumors and associated with prognosis. ZLM-7, SP1, VEGFA and miR-212-3p were associated with BC angiogenesis and proliferation, however the detailed mechanism was not clear. This study aimed to reveal the regulatory mechanism of angiogenesis of BC. Methods BC cell lines were treated with 10 nM ZLM-7 for 8 h. We detected protein expression level by western blot and RNA expression level by qRT-PCR. Overexpression or inhibition of miR-212-3p is performed using miR-212-3p mimics or miR-212-3p inhibitor, Sp1 overexpression using pcDNA3.1 vector. Angiogenesis was analyzed by co-culturing BC cell lines and HUVEC cells. To evaluate regulatory relationship between miR-212-3p and Sp1, dual luciferase assay was performed. Besides, the direct interaction between Sp1 and VEGFA was analyzed by ChIP. Migration and invasion were analyzed by transwell assay and proliferation was detected by clone formation assay. In mice xenograft model developed using BC cells, we also detected angiogenesis marker CD31 through immunohistochemistry. Results ZLM-7 up-regulated miR-212-3p and inhibited invasion, migration, proliferation and angiogenesis of BC, while miR-212-3p inhibitor antagonized such effects. Binding sequence was revealed between miR-212-3p and Sp1, and expression of Sp1 was inhibited by miR-212-3p on both protein and mRNA level. Sp1 could interact with VEGFA and promoted its expression. Overexpression of miR-212-3p inhibited migration, invasion, proliferation and angiogenesis of BC cell lines, while Sp1 overexpression showed the opposite effect and could antagonize these effects of miR-212-3p overexpression. ZLM-7 decreased VEGFA expression, which was rescued by co-transfection with miR-212-3p inhibitor. Similar, ZLM-7 could inhibit tumor growth and angiogenesis through the miR-212-3p/Sp1/VEGFA axis in vivo. Conclusions ZLM-7 could directly up-regulate miR-212-3p in BC. MiR-212-3p could inhibit VEGFA expression through Sp1, thereby inhibiting angiogenesis and progression of BC.

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Caspase cleavage of transcription factor Sp1 enhances apoptosis

Cited by 25 publications

References 76 publications

Bortezomib Targets Sp Transcription Factors in Cancer Cells

Bortezomib Targets Sp Transcription Factors in Cancer Cells

DSB repair pathway choice is regulated by recruitment of 53BP1 through cell cycle-dependent regulation of Sp1

ZLM-7 inhibits the occurrence and angiogenesis of breast cancer through miR-212-3p/Sp1/VEGFA signal axis

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