Sp transcription factor family and its role in cancer

doi:10.1016/j.ejca.2005.08.006

European Journal of Cancer

Volume 41, Issue 16, November 2005, Pages 2438-2448

https://doi.org/10.1016/j.ejca.2005.08.006 Get rights and content

Abstract

Specificity protein 1 (Sp1) and other Sp and Krüppel-like factor (KLF) proteins are members of a family of transcription factors which bind GC/GT-rich promoter elements through three C₂H₂-type zinc fingers that are present at their C-terminal domains. Sp1–Sp4 proteins regulate expression of multiple genes in normal tissues and tumours. There is growing evidence that some Sp proteins play a critical role in the growth and metastasis of many tumour types by regulating expression of cell cycle genes and vascular endothelial growth factor. Sp/KLF proteins are also potential targets for cancer chemotherapy.

Introduction

Specificity protein 1 (Sp1) was the first transcription factor identified and cloned, and shown to be a sequence-specific DNA-binding protein that activated a broad and diverse spectrum of mammalian and viral genes 1, 2, 3, 4, 5. Sp1 protein recognises GC/GT boxes and interacts with DNA through three C₂H₂-type zinc fingers located at the C-terminal domain 6, 7, 8. Based on results of crystal structure and NMR studies, each of the three zinc fingers in Sp1 recognises three bases in one strand, and a single base in the complementary strand of the GC-rich elements where the consensus Sp1 binding site is 5′-(G/T)GGGCGG(G/A)(G/A)(C/T)-3′ 9, 10. A recent NMR study now shows that the more C-terminal zinc finger 1 has reduced specificity and can also bind only two bases in the recognition sequence [11]. This may account for the interactions of Sp1 with diverse GC-rich promoter sequences and for Sp1-dependent regulation of a large number of mammalian genes in normal and transformed cells 12, 13, 14. Although Sp1 binding affinities to non-consensus GC-rich motifs may be lower than for consensus sequences, their functional interactions in regulating gene expression may be highly significant.

Section snippets

Sp family of transcription factors and their expression in tumours

Sp1 is a member of a growing family of nuclear proteins that modulate gene transcription and the Sp/Krüppel-like factors (KLFs) are categorised by their similar modular structures [reviewed in 15, 16, 17, 18, 19, 20]. Sp1–Sp4 form a subgroup (Fig. 1) which contain several distinct overlapping features/regions which include activation domains (AD), the C-terminal zinc finger DNA-binding region, and an inhibitory domain (ID) in Sp3 that is involved in the suppressive activity of Sp3. Sp5–Sp8 are

Regulation of growth promoting and cell survival genes by sp proteins in cancer cells

Sp family proteins regulate basal/constitutive expression of genes involved in multiple functions in both normal and cancerous tissues [18]. Genes that regulate growth and cell cycle progression frequently contain proximal GC-rich promoter sequences, and their interactions with Sp proteins and other transcription factors are critical for their expression. For example, several studies show that VEGF expression in cancer cell lines is regulated through Sp protein interactions with several

Strategies for targeting Sp protein pathways in cancer cells

For many human cancers, Sp protein overexpression is a negative prognostic factor for survival and, not surprisingly, these transcription factors contribute to the proliferative and metastatic tumour phenotype. Strategies for inhibiting Sp-dependent pathways have focused on several approaches which include drugs that inactivate GC-rich DNA motifs, oligonucleotides and peptide nucleic acid–DNA chimeras that specifically interact with Sp1 binding motifs (decoys), and chemicals that modulate Sp

Mechanisms of Sp protein action in cancer cells

The primary mechanism of Sp protein-dependent transactivation in cancer and non-cancer cell lines involves initial binding to GC-rich promoter sequences and subsequent interactions with components of the basal transcription machinery to activate gene expression. This sequence of events is common to many transcription factors; however, Sp-dependent activation of genes is highly complex, dependent on both gene promoter and cell context and on interactions with other nuclear proteins as discussed

Conclusions

Transcription factors are now recognized as targets for development of new anticancer drugs [113], and this review outlines the important role of Sp-dependent gene expression in tumour development, growth and metastasis. The complexity of Sp-dependent regulation of genes in cancer has primarily been reported for Sp1 and to a lesser extent Sp3; however, based on recent reports it is conceivable that Sp4 protein may also be important in some cases. The complexity of Sp protein-dependent

Conflict of interest statement

None declared.

Acknowledgements

Financial support from the National Institutes of Health (ES09106) and the M.D. Anderson Pancreatic Cancer SPORE (P20-CA10193) is gratefully acknowledged.

References (113)

W.S. Dynan et al.
The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter
Cell
(1983)
W.S. Dynan et al.
Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II
Cell
(1983)
J.T. Kadonaga et al.
Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain
Cell
(1987)
J.T. Kadonaga et al.
Promoter-specific activation of RNA polymerase II transcription by Sp1
TIBS
(1986)
P. Bucher
Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences
J Mol Biol
(1990)
V.A. Narayan et al.
Structures of zinc finger domains from transcription factor Sp1. Insights into sequence-specific protein-DNA recognition
J Biol Chem
(1997)
L. Dong et al.
Mechanisms of transcriptional activation of bcl-2 gene expression by 17β-estradiol in breast cancer cells
J Biol Chem
(1999)
J.R. Schultz et al.
Estrogen receptor α and Sp1 regulate progesterone receptor gene expression
Mol Cell Endocrinol
(2003)
L. Lania et al.
Transcriptional regulation by the Sp family proteins
Int J Biochem Cell Biol
(1997)
P. Bouwman et al.
Regulation of the activity of Sp1-related transcription factors
Mol Cell Endocrinol
(2002)

G. Suske

The Sp-family of transcription factors

Gene

(1999)

S. Safe et al.

Nuclear receptor-mediated transactivation through interaction with Sp proteins

Prog Nucleic Acid Res Mol Biol

(2004)

C. Rachez et al.

Mediator complexes and transcription

Curr Opin Cell Biol

(2001)

M. Marin et al.

Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation

Cell

(1997)

H. Gollner et al.

Impaired ossification in mice lacking the transcription factor Sp3

Mech Dev

(2001)

D.M. Supp et al.

Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility

Dev Biol

(1996)

M. Ryuto et al.

Induction of vascular endothelial growth factor by tumour necrosis factor alpha in human glioma cells. Possible roles of SP-1

J Biol Chem

(1996)

C. Ji et al.

Multiple and essential Sp1 binding sites in the promoter for transforming growth factor-β type I receptor

J Biol Chem

(1997)

S. Ammanamanchi et al.

Induction of transforming growth factor-β receptor type II expression in estrogen receptor-positive breast cancer cells through SP1 activation by 5-aza-2′-deoxycytidine

J Biol Chem

(1998)

Y. Liu et al.

The role of Sp1 in the differential expression of transforming growth factor-β receptor type II in human breast adenocarcinoma MCF-7 cells

J Biol Chem

(2000)

S. Ammanamanchi et al.

Sp3 is a transcriptional repressor of transforming growth factor-β receptors

J Biol Chem

(2001)

L. Sun et al.

Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells

J Biol Chem

(1994)

E. Castro-Rivera et al.

Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements

J Biol Chem

(2001)

B. Saville et al.

Ligand-, cell- and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements

J Biol Chem

(2000)

M. Abdelrahim et al.

Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells

J Biol Chem

(2002)

I.J. Arinze et al.

Sp family of transcription factors is involved in valproic acid-induced expression of Gα_i2

J Biol Chem

(2003)

J. Wu et al.

Molecular mechanism of inhibition of survivin transcription by the GC-rich sequence-selective DNA binding antitumour agent, hedamycin: evidence of survivin down-regulation associated with drug sensitivity

J Biol Chem

(2005)

Y.M. Chae et al.

Sp1-decoy oligodeoxynucleotide inhibits high glucose-induced mesangial cell proliferation

Biochem Biophys Res Commun

(2004)

X. Xu et al.

Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides

J Biol Chem

(2001)

M. Borgatti et al.

Transcription factor decoy molecules based on a peptide nucleic acid (PNA)-DNA chimera mimicking Sp1 binding sites

J Biol Chem

(2003)

S. Gately et al.

Multiple roles of COX-2 in tumour angiogenesis: a target for antiangiogenic therapy

Semin Oncol

(2004)

A.J. Courey et al.

Synergistic activation by the glutamine-rich domains of human transcription factor Sp1

Cell

(1989)

S. Cao et al.

KLF11-mediated repression antagonizes Sp1/sterol-responsive element-binding protein-induced transcriptional activation of caveolin-1 in response to cholesterol signaling

J Biol Chem

(2005)

T. Saito et al.

Novel transcriptional regulation of the human CYP3A7 gene by Sp1 and Sp3 through nuclear factor κ B-like element

J Biol Chem

(2001)

K.L. Wright et al.

Major histocompatibility complex class II-associated invariant chain gene expression is up-regulated by cooperative interactions of Sp1 and NF-Y

J Biol Chem

(1995)

G. Gill et al.

Eukaryotic coactivators associated with the TATA box binding protein

Curr Opin Genet Dev

(1992)

T. Hoey et al.

Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators

Cell

(1993)

E. Rojo-Niersbach et al.

Genetic dissection of hTAF (II)130 defines a hydrophobic surface required for interaction with glutamine-rich activators

J Biol Chem

(1999)

M. Ito et al.

Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators

Mol Cell

(1999)

D. Kardassis et al.

c-Jun transactivates the promoter of the human p21^WAF1/Cip1 gene by acting as a superactivator of the ubiquitous transcription factor Sp1

J Biol Chem

(1999)

C.H. Wang et al.

Transcriptional repression of p21^{Waf1/Cip1/Sdi1} gene by c-jun through Sp1 site

Biochem Biophys Res Commun

(2000)

J. Milanini-Mongiat et al.

Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription

J Biol Chem

(2002)

W.S. Dynan et al.

Control of eukaryotic messenger RNA synthesis by sequence-specific DNA-binding proteins

Nature

(1985)

M.R. Briggs et al.

Purification and biochemical characterization of the promoter- specific transcription factor, Sp1

Science

(1986)

J.T. Kadonaga et al.

Distinct regions of Sp1 modulate DNA binding and transcriptional activation

Science

(1988)

N.P. Pavletich et al.

Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 Å

Science

(1991)

S. Oka et al.

NMR structure of transcription factor Sp1 DNA binding domain

Biochemistry

(2004)

R. Duan et al.

Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation

Endocrinology

(1998)

S. Philipsen et al.

A tale of three fingers: the family of mammalian Sp/XKLF transcription factors

Nucleic Acids Res

(1999)

A.R. Black et al.

Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer

J Cell Physiol

(2001)

Cited by (431)

Modulation of Krüppel-like factors (KLFs) interaction with their binding partners in cancers through acetylation and phosphorylation
2024, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Post-translational modifications (PTMs) of transcription factors regulate transcriptional activity and play a key role in essentially all biological processes and generate indispensable insight towards biological function including activity state, subcellular localization, protein solubility, protein folding, substrate trafficking, and protein-protein interactions. Amino acids modified chemically via PTMs, function as molecular switches and affect the protein function and characterization and increase the proteome complexity. Krüppel-like transcription factors (KLFs) control essential cellular processes including proliferation, differentiation, migration, programmed cell death and various cancer-relevant processes. We investigated the interactions of KLF group-2 members with their binding partners to assess the role of acetylation and phosphorylation in KLFs on their binding affinity. It was observed that acetylation and phosphorylation at different positions in KLFs have a variable effect on binding with specific partners. KLF2-EP300, KLF4-SP1, KLF6-ATF3, KLF6-JUN, and KLF7-JUN show stabilization upon acetylation or phosphorylation at variable positions. On the other hand, KLF4-CBP, KLF4-EP300, KLF5-CBP, KLF5-WWP1, KLF6-SP1, and KLF7-ATF3 show stabilization or destabilization due to acetylation or phosphorylation at variable positions in KLFs. This provides a molecular explanation of the experimentally observed dual role of KLF group-2 members as a suppressor or activator of cancers in a PTM-dependent manner.
A microwell platform for high-throughput longitudinal phenotyping and selective retrieval of organoids
2023, Cell Systems
Organoids are powerful experimental models for studying the ontogeny and progression of various diseases including cancer. Organoids are conventionally cultured in bulk using an extracellular matrix mimic. However, bulk-cultured organoids physically overlap, making it impossible to track the growth of individual organoids over time in high throughput. Moreover, local spatial variations in bulk matrix properties make it difficult to assess whether observed phenotypic heterogeneity between organoids results from intrinsic cell differences or differences in the microenvironment. Here, we developed a microwell-based method that enables high-throughput quantification of image-based parameters for organoids grown from single cells, which can further be retrieved from their microwells for molecular profiling. Coupled with a deep learning image-processing pipeline, we characterized phenotypic traits including growth rates, cellular movement, and apical-basal polarity in two CRISPR-engineered human gastric organoid models, identifying genomic changes associated with increased growth rate and changes in accessibility and expression correlated with apical-basal polarity.
A record of this paper’s transparent peer review process is included in the supplemental information.
Secoisolariciresinol diglucoside Ameliorates Osteoarthritis via Nuclear factor-erythroid 2-related factor-2/ nuclear factor kappa B Pathway: In vitro and in vivo experiments
2023, Biomedicine and Pharmacotherapy
Osteoarthritis (OA) is an age-related joint disease in which inflammation and extracellular matrix (ECM) degradation play a crucial role in the destruction of articular cartilage. Secoisolariciresinol diglucoside (SDG), the main lignan in wholegrain flaxseed, which has been reported to remarkably suppress inflammation and oxidative stress, may have potential therapeutic value in OA. In this study, the effect and mechanism of SDG against cartilage degeneration were verified in the destabilization of the medial meniscus (DMM) and collagen-induced (CIA) arthritis models and interleukin-1β (IL-1β)-stimulated osteoarthritis chondrocyte models. From our experiments, SDG treatment downregulated the expression of pro-inflammatory factors induced by IL-1β in vitro, including inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX2), tumor necrosis factor (TNF-α), and interleukin 6 (IL-6). Additionally, SDG promoted the expression of collagen II (COL2A1) and SRY-related high-mobility-group-box gene 9(SOX9), while suppressing the expression of a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5) and matrix metalloproteinases 13(MMP13), which leads to catabolism. Consistently, in vivo, SDG has been identified to have chondroprotective effects in DMM-induced and collagen-induced arthritis models. Mechanistically, SDG exerted its anti-inflammation and anti-ECM degradation effects by activating the Nrf2/HO-1 pathway and inhibiting the nuclear factor kappa B (NF-κB) pathway. In conclusion, SDG ameliorates the progression of OA via the Nrf2/NF-κB pathway, which indicates that SDG may have therapeutic potential for OA.
The role of KLF transcription factor in the regulation of cancer progression
2023, Biomedicine and Pharmacotherapy
Kruppel-like factors (KLFs) are a family of zinc finger transcription factors that have been found to play an essential role in the development of various human tissues, including epithelial, teeth, and nerves. In addition to regulating normal physiological processes, KLFs have been implicated in promoting the onset of several cancers, such as gastric cancer, lung cancer, breast cancer, liver cancer, and colon cancer. To inhibit cancer progression, various existing medicines have been used to modulate the expression of KLFs, and anti-microRNA treatments have also emerged as a potential strategy for many cancers. Investigating the possibility of targeting KLFs in cancer therapy is urgently needed, as the roles of KLFs in cancer have not received enough attention in recent years. This review summarizes the factors that regulate KLF expression and function at both the transcriptional and posttranscriptional levels, which could aid in understanding the mechanisms of KLFs in cancer progression. We hope that this review will contribute to the development of more effective anti-cancer medicines targeting KLFs in the future.
Aberrant transcription factors in the cancers of the pancreas
2022, Seminars in Cancer Biology
Transcription factors (TFs) are essential for proper activation of gene during the process of organogenesis, differentiation, lineage specificity. Reactivation or dysregulation of TFs regulatory networks could lead to deformation of organs, diseases including various malignancies. Currently, understanding the mechanism of oncogenesis became a necessity for the development of targeted therapeutic strategy for different cancer types. It is evident that many TFs go awry in cancers of the pancreas such as pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PanNENs). These mutated or dysregulated TFs abnormally controls various signaling pathways in PDAC and PanNENs including RTK, PI3K-PTEN-AKT-mTOR, JNK, TGF-β/SMAD, WNT/β-catenin, SHH, NOTCH and VEGF which in turn regulate different hallmarks of cancer. Aberrant regulation of such pathways have been linked to the initiation, progression, metastasis, and resistance in pancreatic cancer. As of today, a number of TFs has been identified as crucial regulators of pancreatic cancer and a handful of them shown to have potential as therapeutic targets in pre-clinical and clinical settings. In this review, we have summarized the current knowledge on the role and therapeutic usefulness of TFs in PDAC and PanNENs.
Chromatin modifiers – Coordinators of estrogen action
2022, Biomedicine and Pharmacotherapy
A group of hormones, called estrogens, are pivotal drivers of various physiological processes. Expectedly, estrogen-driven actions are also relevant modulators of pathophysiological changes, including cancer. Different transcriptional and tissue-specific responses are elicited mainly by two estrogen receptor (ER) isoforms, ERα and ERβ. Although perturbations of ER subtype-specific expression are correlated with clinical outcomes of cancer, the result strongly depends on co-regulators. Co-regulator acts as a ‘bridge’ that helps form large protein complexes to modulate transcriptional activity on target gene chromatin. ERs, as transcription factors, may be positively or negatively influenced by the utilisation of different tissue-specific co-regulators. These co-regulators are enzymes that create the epigenetic landscape of histone and DNA modifications, along with proteins that read these modifications and ATP-dependent chromatin remodelers. This review provides an overview and update on ER-driven responses, focusing on the complex interaction between ERs and chromatin modifiers, and discusses how chromatin accessibility and epigenetic modifications contribute to ER recruitment and transactivation.

View all citing articles on Scopus

View full text

Sp transcription factor family and its role in cancer

Abstract

Introduction

Section snippets

Sp family of transcription factors and their expression in tumours

Regulation of growth promoting and cell survival genes by sp proteins in cancer cells

Strategies for targeting Sp protein pathways in cancer cells

Mechanisms of Sp protein action in cancer cells

Conclusions

Conflict of interest statement

Acknowledgements

Cell

Cell

Cell

TIBS

J Mol Biol

J Biol Chem

J Biol Chem

Mol Cell Endocrinol

Int J Biochem Cell Biol

Mol Cell Endocrinol

Gene

Prog Nucleic Acid Res Mol Biol

Curr Opin Cell Biol

Cell

Mech Dev

Dev Biol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Semin Oncol

Cell

J Biol Chem

J Biol Chem

J Biol Chem

Curr Opin Genet Dev

Cell

J Biol Chem

Mol Cell

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

Control of eukaryotic messenger RNA synthesis by sequence-specific DNA-binding proteins

Nature

Purification and biochemical characterization of the promoter- specific transcription factor, Sp1

Science

Distinct regions of Sp1 modulate DNA binding and transcriptional activation

Science

Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 Å

Science

NMR structure of transcription factor Sp1 DNA binding domain

Biochemistry

Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation

Endocrinology

A tale of three fingers: the family of mammalian Sp/XKLF transcription factors

Nucleic Acids Res

Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer

J Cell Physiol