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Acta Biochim Biophys
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doi:10.1111/j.1745-7270.2008.00439.x |
Roles of Krüppel-like factor 4 in normal
homeostasis, cancer and stem cells
Paul M Evans and Chunming Liu*
Department of Biochemistry and Molecular
Biology, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch,
Galveston, Texas 77555-1448, USA
Received: April 20,
2008
Accepted: May 15,
2008
This work was
supported by the grants from the Sealy Center for Cancer Cell Biology, the National
Institutes of Health (No. T32CA117834), and the Charlotte Geyer Foundation
*Corresponding
author: Tel, 1-409-747-1909; E-mail, [email protected]
Krüppel-like factor 4 (KLF4) is a zinc
finger-type transcription factor expressed in a variety of tissues, including
the epithelium of the intestine and the skin, and it plays an important role in
differentiation and cell cycle arrest. Depending on the gene targeted, KLF4 can
both activate and repress transcription. Moreover, in certain cellular
contexts, KLF4 can function as a tumor suppressor or an oncogene. Finally, KLF4
is important in reprogramming differentiated fibroblasts into inducible
pluripotent stem cells, which highly resemble embryonic stem cells. This review
summarizes what is known about the diverse functions of KLF4 as well as their
molecular mechanisms.
Keywords Krüppel-like factor 4; colorectal cancer; stem cell
Krüppel-like factor 4 (KLF4) is a transcription factor expressed in a wide variety of tissues in humans, including the intestine and the skin, which is important for many different physiologic processes, including development, differentiation, and maintenance of normal tissue homeostasis. KLF4 is a bi-functional transcription factor that can either activate or repress transcription using different mechanisms, depending on the target gene. In addition, KLF4 can function as an oncogene or a tumor suppressor depending on the type of cancer involved. In concert with three other transcription factors, KLF4 can reprogram differentiated fibroblasts into a state resembling embryonic stem cells in every possible manner tested so far. This review will provide a detailed summary of what is currently known about KLF4 and its role in the homeostasis of tissues, in cancer and in stem cell reprogramming.
The Krüppel-like Factor Family
Krüppel-like factors are a family of transcription factors that play important roles in many fundamental biologic processes, including development, proliferation, differentiation and apoptosis (Fig. 1). Krüppel-like factor family members contain three C-terminal C2H2-type zinc fingers that bind DNA. They were named “Krüppel-like” due to strong homology in this region with the Drosophila gene product Krüppel, which is important in segmentation of the developing embryo. Genetic deletion of Krüppel results in complete absence of the thoracic and anterior abdominal segments [1]. KLF4 was cloned independently by two groups, and given two different names: gut-enriched Krüppel-like factor due to the fact that it was found to be highly expressed in the intestine [2], and epithelial zinc finger due to its high expression in the skin epithelium [3]. It was later renamed KLF4 to avoid confusion, as expression of KLF4 is also detectable in the lung, skin, testis [2-5], thymus [6], cornea [7], cardiac myocytes [8], and lymphocytes [9]. In addition, KLF4 is important in development, as it is detectable in the mouse embryo, with the highest expression occurring in the later stages [3,4].
Roles of KLF4 in Homeostasis of the Colonic Epithelium
The colonic epithelium consists of three major types of differentiated cells: enterocytes, goblet cells and enteroendocrine cells. Actively proliferating cells reside at the base of the crypts and migrate towards the luminal surface as they differentiate, eventually to be sloughed off. KLF4 inhibits proliferation and promotes differentiation; consistent with this role, expression of KLF4 is greatest near the luminal surface and gradually decreases toward the base of the crypts [2,10]. Klf4-/- mice lack goblet cells, which does not affect the total number of enterocytes, suggesting that KLF4 may be specifically required for goblet cell differentiation [11]. In addition, KLF4 can interact with b-catenin and antagonize Wnt signaling [10], a key pathway in driving proliferation of the intestinal epithelium [12-14]. Thus, KLF4 may also be important in mediating the switch from transit-amplifying cells to the various differentiated cell types in the colonic crypts.
Butyrate is constantly produced in the colon by bacterial fermentation of dietary fiber in the intestine [15], and it can induce expression of KLF4 [5,16]. In cell culture, butyrate stimulates expression of the enterocyte-specific marker intestinal alkaline phosphatase [17], and induces colon cancer cells to acquire a more differentiated, enterocyte-like phenotype [18]. KLF4 positively regulates expression of intestinal alkaline phosphatase [19,20], and overexpression of KLF4 in cell culture inhibits proliferation [2,5].
KLF4 appears to have inhibitory effect on a wide variety of cellular processes, including protein and cholesterol synthesis, transcription, cell growth and DNA repair [21,22]. Consistent with its anti-proliferative role, KLF4 simultaneously induces the expression of cyclin-dependent kinase inhibitor proteins p21Cip1/WAF1 and p57Kip2 [21,23–25], and represses the expression of Cyclin D1 [5,26,27], Cyclin D2 [28], Cyclin E [29], and Cyclin B1 [30] (Fig. 2). In addition, KLF4 represses expression of ornithine decarboxylase [7,31], an enzyme involved in the production of a class of molecules known as polyamines, which are also important in proliferation. KLF4 is required for both the G1/S-phase and G2/M-phase checkpoints [30,32,33]. Finally, KLF4 represses expression of p53 and may be important in determining whether cells decide to undergo apoptosis or cell cycle arrest [34].
Roles in
other Homeostasis of Other Tissues
Although the importance of KLF4 in the intestine is well characterized, increasing evidence demonstrates its importance in other organs and tissues as well. For example, KLF4-/- mice die of dehydration soon after birth due to defects in the epidermal barrier of the skin [35], yet targeted overexpression of KLF4 results in early formation of the epithelial permeability barrier [36]. These data clearly implicate KLF4 as an important molecule in differentiation of the skin epithelium.
Furthermore, overexpressed KLF4 can synergize with maternally injected corticosteroids in accelerating the formation of the skin barrier. This is likely due to overlap between the genes targeted by KLF4 and the glucocorticoid receptor [37]. The utility of glucocorticoids in lung maturation of premature infants is well-established [38], thus it might be interesting to determine whether KLF4 or possibly other Krüppel-like factors could synergize with glucocorticoids in fetal lung maturation as well. Also, in the developing fetus, KLF4 synergizes with Sp1 in up-regulating expression of PSG-5, a protein secreted into the maternal circulation by the placenta [39]. PSG-5 is thought be required for maintenance of a term pregnancy and may protect the fetus from attack by the maternal immune system. In addition, KLF4 and PSG-5 have closely overlapping patterns of expression in the placenta, suggesting an in vivo role for KLF4 in the regulation of PSG-5 expression [40].
Human KLF4 was isolated from an umbilical vein complementary DNA library and is expressed in the vascular endothelium [41]. Expression of KLF4 is induced by shear stress in endothelial cells [42], whereas KLF4 appears to block differentiation and is expressed at low levels in differentiated arterial smooth muscle cells [43]. However, expression of KLF4 is rapidly up-regulated in smooth muscle cells in response to vascular injury [44].
Overexpression of KLF4 in a pro-myelocytic cell line increases the expression of monocyte markers, whereas knockdown of KLF4 decreases TPA-induced overexpression of these same markers. In addition, KLF4-/- hematopoietic stem cells less frequently differentiate into monocytes [45]. When fetal liver cells from KLF4-/- mice were transplanted into lethally irradiated wild-type mice, they had undetectable levels of circulating inflammatory monocytes [46]. Thus, KLF4 appears to be important for both resident and inflammatory monocyte differentiation.
KLF4 is highly expressed in the corneal epithelium, where it is important in differentiation. Targeted deletion of KLF4 in the eye results in corneal fragility, edema and a lack of goblet cells in the conjunctiva [47]. In a cell culture model of adipocyte differentiation using 3T3-L1 cells, short interfering RNA-mediated knockdown of KLF4 completely blocked expression of several phenotypic markers of differentiated adipocytes [48]. Collectively, these data strongly implicate KLF4 as a factor involved in the differentiation of many tissues.
Roles of KLF4 in Cancers
As an anti-proliferative factor expressed in differentiated epithelia, it seems logical that KLF4 might act as a tumor suppressor, and indeed this appears to be the case in the gastrointestinal tract [49,50]. However, recent evidence suggests that KLF4 might also act as an oncogene in certain contexts [51]. This section will investigate these two contrasting roles.
KLF4 as a tumor suppressor
Increasing evidence implicates KLF4 as a tumor suppressor in the intestinal epithelium. In human colorectal carcinoma, expression of KLF4 is down-regulated, with evidence of both hypermethylation and loss of heterozygosity [52-54]. However, no association has been found between down-regulation of KLF4 and tumor staging or 5-year survival in patients with metastatic carcinoma, suggesting that loss of KLF4 in colorectal cancer may be an early event [53,54].
Examination of KLF4 expression in mouse models of colorectal cancer has yielded similar results. The APCmin/+ mouse develops hundred of intestinal adenomas early in life and is a widely used model of intestinal tumorigenesis [55,56]. In adenomas from these mice, KLF4 is down-regulated, with expression inversely related to the size of the tumor [4,57]. As APC is a critical component of the Wnt/b-catenin pathway and APCmin/+ mice express a truncated form of the APC protein, these mice have deregulated Wnt signaling in their intestine [58,59]. Interestingly, KLF4 can interact with b-catenin in the nucleus and repress Wnt signaling in vivo, as well as inhibit tumor growth in tumor xenografts [10]. In addition, crossing APCmin/+ mice with KLF4+/- heterozygotes resulted in significantly more adenomas than in APCmin/+ mice alone [60]. Notably, this phenotype was similar to that found with another double mutant, APCMin/+/TCF-1-/-. The most abundant isoform of TCF-1 expressed in the intestine is also an antagonist of Wnt/b-catenin signaling, suggesting that an important effect of decreased KLF4 expression during colorectal tumorigenesis may be de-repression of Wnt signaling.
In human colon cancer cell lines, several point mutations have been found in the KLF4 gene. One mutation had a significant effect on the ability to activate a p21Cip1/WAF1 reporter construct in NIH3T3 cells [52]. However, an investigation to identify mutations in tissue samples of human colorectal cancers has not yet been performed. In the HCT116 colorectal cancer cell line, KLF4 is required to prevent centrosome amplification after gamma-irradiation, and loss of KLF4 may promote chromosomal instability [29]. In addition, KLF4 represses expression of the enzyme ornithine decarboxylase [31], a proto-oncogene that alone is sufficient to transform NIH3T3 cells [61]. Collectively, these data strongly implicate KLF4 as a tumor suppressor in the colon.
Strong evidence also implicates KLF4 as a tumor suppressor in the gastric epithelium. Similar to colorectal cancer, KLF4 is down-regulated in gastric cancer, with evidence of hypermethylation and loss of heterozygosity [62-64]. Moreover, targeted loss of the KLF4 gene in the gastric mucosa of mice results in pre-cancerous changes in the stomach [65]. In examining both normal and cancerous gastric mucosal tissue from humans, one study found an inverse relationship between the expression of KLF4 and Sp1, a distantly related Krüppel-like factor family member (Fig. 1) [62]. In addition, the same study found that in gastric cancer cell lines, KLF4 can directly repress the expression of Sp1. Given that strong expression of Sp1 is correlated with poor survival in gastric cancer [66], loss of KLF4 may contribute to gastric cancer progression.
In addition to gastric and colorectal cancer, KLF4 is down-regulated in esophageal cancer [67,68], bladder cancer [69], non-small-cell lung carcinoma [70], and leukemia [71,72].
KLF4 as an oncogene
Although these data clearly demonstrate that KLF4 can act as tumor suppressor in multiple tissues, the possibility that KLF4 might be an oncogene as well was first demonstrated in the late 1990s. Using E1A-immortalized rat kidney epithelial cells to screen for factors that could induce transformation, KLF4 was identified. Moreover, KLF4-transformed rat kidney epithelial cells could produce tumors in xenografted mice [73]. KLF4 is overexpressed in laryngeal squamous cell carcinoma as an early event in its progression [73]. Expression of KLF4 is increased in ductal carcinoma of the breast [74], and increased nuclear staining is associated with a more aggressive phenotype and poorer prognosis [75]. In the skin, overexpression of KLF4 results in hyperplasia and dysplasia [76], eventually leading to squamous cell carcinoma [77].
Whether KLF4 acts as a tumor suppressor or an oncogene is likely due to differences in cell context, expression patterns of other genes and the chromatin environment of individual cells. However, the mechanism to explain these differences fully is unknown. A recent study that found that KLF4 could override RasV12-induced senescence in primary fibroblasts and induce transformation provided some insight [34]. Additionally, this study demonstrated that the status of p21Cip1/WAF1, a transcriptional target of KLF4, determined whether overexpression of KLF4 induced transformation or resulted in cell cycle arrest. Overexpression of KLF4 alone increases expression of p21Cip1/WAF1 and results in cell cycle arrest. However, the addition of RasV12 resulted in inhibition of p21Cip1/WAF1 expression, allowing KLF4’s ability to repress p53 to predominate. Repression of p53 effectively blocked apoptosis and, in concert with the decreased expression of p21Cip1/WAF1, eventually led to transformation. Thus, KLF4 can be added to a growing list of genes that have multiple, context-dependent roles in cancer, including CDKN1A (p21), transforming growth factor-b, Ras and NOTCH1 genes [51].
Roles of KLF4 in Stem Cell Renewal and
Reprogramming
Recently, it was found that overexpression of KLF4, in combination with three other transcription factors, could transform mouse fibroblasts into a state resembling embryonic stem cells (ES cells). These cells have been termed “inducible pluripotent stem cells” (iPS cells) [78]. By replacing the open reading frame of Fbx15, a non-essential marker of ES cells, with a neomycin resistance gene, it was hypothesized that neomycin-resistant colonies might have somehow reprogrammed themselves into ES cells. After screening a short list of potential factors, it was found that the simultaneous infection of retroviruses expressing Oct3/4, Sox2, c-Myc and KLF4 were able to produce resistant clones. These cells could form teratomas that contained differentiated tissues from all three germ layers, confirming their pluripotency. This approach was further refined by screening for neomycin resistance based on Nanog or Oct4 expression instead of Fbx15 expression. Unlike Fbx15-iPS cells, Nanog and Oct4-iPS could produce chimeric mice, and generate live late-term embryos when injected into tetraploid blastocysts [79-81]. Thus, Nanog- and Oct4-iPS are even more stringent tests of pluripotency than Fbx15-iPS cells.
Researchers are currently trying to gain a better understanding of the molecular events that occur during stem cell reprogramming as well as the precise role of the four individual factors required. The importance of Oct3/4 and Sox2 in ES cell renewal is well established [82]. What is less clear is the function of the other two factors that make up the "magic brew": c-Myc and KLF4. One possibility is that c-Myc and KLF4 confer increased proliferative capacity on potential iPS cells, since both can function as oncogenes [83]. Since c-Myc regulates a significant number of genes, its function may be to affect global changes in the chromatin environment by recruiting histone acetyl-transferase complexes. According this model, KLF4 may then function to inhibit apoptosis induced by overexpression of c-Myc. KLF4 represses c-Myc expression in colon cancer cells by inhibiting Wnt signaling [10]. While the role of Wnt signaling in iPS cells remains unresolved, c-Myc may provide a balance for KLF4.
Overexpression of KLF4 in ES cells inhibited differentiation in erythroid progenitors and increased their capacity to generate secondary embryoid bodies, suggesting a role for KLF4 in self-renewal [84]. In concert with Oct3/4 and Sox2, KLF4 activates expression of Lefty1, a gene expressed in ES cells but lost during differentiation [85]. In addition, KLF4-null mice survive to term and have no detectable defects during embryogenesis in their pluripotent stem cell population [11,35], suggesting that KLF4 may be dispensable in normal ES cells. More recently, human iPS have been produced using a slightly different mix of factors, substituting Nanog and LIN28 for c-Myc and KLF4 [86], further calling into question the overall importance of c-Myc and KLF4. It has even been suggested that c-Myc and KLF4 are merely molecular catalysts, in that they might accelerate or increase the efficiency of the reprogramming process, but are otherwise not absolutely required [87].
However, a recent study has found that KLF4’s function in ES cell self-renewal is partially redundant; knockdown of KLF4, KLF2 and KLF5, but not any one individually, resulted in spontaneous ES cell differentiation [88]. In addition, significant overlap was found between genes regulated by Nanog and the three Krüppel-like factors. Clearly, a complete understanding of the role of KLF4 in ES cell self-renewal and iPS cell reprogramming awaits further study
Molecular
Mechanisms of KLF4
Human and mouse KLF4 are 470 and 483 amino acids in length, respectively, and produce a 55 kDa protein. KLF4 can be roughly divided into three separate domains: a N-terminal activation domain [3,41,89], a central repressive domain [41], and a C-terminal DNA-binding domain (Fig. 3). The DNA-binding domain consists of three successive zinc fingers, each containing an anti-parallel b-sheet, followed by a short loop and an a-helix. Two cysteines within the b-sheet and two histidines within the a-helix work together to coordinate a single zinc ion, which stabilizes the fold. Each zinc finger interacts with three consecutive nucleotides on a target DNA sequence, and the sequence specificity of a zinc finger protein can be increased simply by adding zinc fingers [90].
In general, KLF4 interacts with GT-rich or CACCC elements on target genes [41,91]. Although one report suggests that KLF4 prefers to bind a RRGGYGY sequence (where R=A/G and Y=C/T) [92], it is still not clear whether this is a true consensus in vivo. KLF4 is exclusively nuclear, like many other transcription factors, and appears to contain two discrete nuclear localization sequences: a basic hexapeptide sequence of a N-terminal to the three C-terminal zinc fingers and a sequence contained within the first two zinc fingers themselves [93].
Given the large number of genes regulated by KLF4, it is not surprising that the expression of KLF4 is highly regulated (Table 1). In the colon cancer cell line HCT116, KLF4 has a half-life of only 2 h and is quickly degraded by the proteasome [94]. However, a variety of stimuli can induce KLF4 expression, including serum starvation, contact inhibition [3], interferon-g [31,95], sodium butyrate [5,16], cAMP [48], gastrin [96], DNA damage [24,33], and oxidative stress [8,25]. The precise mechanism of how the majority these stimuli increase the expression of KLF4 is unclear, although possibilities include increased transcription of the KLF4 gene, increased mRNA stability and/or increased protein stability.
Although much remains to be known about how KLF4 expression is regulated, several transcription factors have been found to regulate its promoter. For example, p53 transactivates the KLF4 gene, and p53 is required for the induction of KLF4 after DNA damage [24,33]. CDX2, another protein important in differentiation of the intestinal epithelium, can activate a KLF4 reporter construct [97]. This suggests that KLF4 may act downstream of CDX2, although more work is necessary to demonstrate this in vivo. KLF4 up-regulates its own expression by binding to its promoter, whereas KLF5 inhibits KLF4 expression and blocks the binding of KLF4 to its promoter [98]. Although KLF4 and KLF5 are closely related transcription factors, expression of KLF5 is in a completely opposite pattern in the colonic intestine, with the strongest expression found in the actively proliferating cells at the base of the crypts; expression is absent in differentiated cells at the luminal surface [99,100]. In fact, KLF4 and KLF5 have several antagonizing roles in the intestinal epithelium [49].
Mechanisms of activation
A major function of KLF4 is to activate transcription of target genes (Table 2). Consistent with this function, the N-terminus of KLF4 contains a strong transactivation domain [3,41,89]. This domain alone, when directly fused to its three C-terminal zinc fingers, is sufficient to activate a synthetic reporter construct [89]. In addition, the N-terminal domain interacts with the transcriptional co-activators p300/CBP, which is required for its function, as point mutations that block interactions with CBP also completely abrogate its ability to activate transcription [20,89]. p300/CBP are histone acetyltransferase proteins, and recruitment of p300/CBP results in an increase in localized histone acetylation at the promoter. Acetylation of histones facilitates the recruitment of other transcription factors as well as the basal transcriptional machinery. In addition, KLF4 itself is acetylated by p300/CBP at lysine residues 225 and 229. Mutation of these two lysines to arginine significantly decreases the ability of KLF4 to transactivate target genes and to inhibit proliferation [20], suggesting that acetylation of KLF4 is important for its function.
One report found that KLF4 can interact with Tip60, a bi-functional cofactor that contains intrinsic histone acetyltransferase activity, but it can also recruit HDAC7 [96]. Tip60 is a co-activator for several nuclear hormone receptors and APP [101,102], but appears to function as a co-repressor for STAT3 by recruiting HDAC7 [103]. Krox20, another zinc finger protein, can directly interact with KLF4 and synergistically activate the C/EBPb gene in 3T3-L1 cells [48]. KLF4 interacts with the NF-kB subunit p65/RelA and synergistically activates expression of inducible nitric oxide synthase [104]. Thus, the mechanisms of transactivation mediated by KLF4 may be gene dependent.
Mechanism of repression
One mechanism for repression by a transcription factor is to simple competition with an activator for binding to a target DNA sequence. This mechanism is known as a form of passive repression. On the CYP1A1, HDC, and Sp1 genes, KLF4 binds to a sequence overlapping that recognized by the activator Sp1, displacing Sp1 from the promoter and resulting in repression of the target gene [62,105,106]. Since Sp1 is ubiquitously expressed and positively regulates many genes [107], it is likely this mechanism is used by KLF4 to repress many of its target genes.
GAL4 fusion assays demonstrate that KLF4 contains central repressive domain in addition to its more fully characterized transactivation domain [41]. This suggests that KLF might actively repress expression of some genes, in addition to or instead of passive repression via competition with a transcriptional activator. In KLF4-mediated repression of the CD11d gene, KLF4 interacts with and recruits HDAC1 and HDAC2 [108], whereas KLF4 represses Cyclin B1 by specifically recruiting HDAC3 [20]. On the TP53 gene, MUC1-C recruits KLF4, as well as HDAC1 and HDAC3, to mediate repression [109]. KLF4 inhibits Smad3-mediated activation of PAI-1 by directly competing with Smad3 for p300 binding [104]. Finally, KLF4 represses transcriptional targets of Wnt signaling by directly interacting with b-catenin/TCF-4 [10]. These data strongly suggest that KLF4-mediated activation and repression is complex and gene-dependent.
Final Thoughts
KLF4 is complex transcription factor that, depending on the context, can act as a transcriptional activator, a transcriptional repressor, an oncogene, and a tumor suppressor. In considering such a transcription factor, questions arise as to how it can switch between these modes and what molecular mechanisms govern its function in normal cells, in cancer and in stem cell reprogramming. Although this review discusses much of what is already known in regard to these issues, more work is needed to fully understand them. Attaining a greater understanding of the molecular function of KLF4 will ultimately provide a deeper insight into these many different fundamental processes.
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