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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:2456S-2460S, July 2003

Supplement: Nutritional Genomics and Proteomics in Cancer Prevention

ZBP-89 Mediates Butyrate Regulation of Gene Expression1 ,2

Juanita L. Merchant*,{dagger},3, Longchuan Bai* and Morihiro Okada*

Departments of * Internal Medicine and {dagger} Physiology, University of Michigan, Ann Arbor, MI 48109

3 To whom correspondence should be addressed. E-mail: merchanj{at}umich.edu.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Inducible p53-independent regulation of the cyclin-dependent kinase inhibitor p21Waf1 transcription is mediated through its proximal GC-rich sites. Prior studies have shown that Sp1, Sp3 and the histone acetyltransferase coactivator p300 are components of the complexes that bind to these sites. Although Sp1 and Sp3 collaborate with p300, a direct interaction between Sp1 and p300 does not occur. Zinc-finger binding protein-89 (ZBP-89, also known as BFCOL1, BERF-1 and ZNF-148) is a Krüppel-type zinc-finger transcription factor that binds to the same GC-rich sequences as Sp1. We sought to determine whether ZBP-89 is a target of p300 during butyrate induction of p21Waf1. This review summarizes the evidence that supports a crucial role for ZBP-89 in butyrate regulation of p21Waf1. Adenovirus-mediated expression of ZBP-89 in HT-29 cells reveals that ZBP-89 potentiates butyrate induction of endogenous p21Waf1 gene expression. DNA-protein interaction assays demonstrate that Sp1, Sp3 and ZBP-89 bind the p21Waf1 promoter at -245 to -215. Coprecipitation assays reveal that p300 preferentially binds to the N-terminus of ZBP-89. ZBP-89 also induces p21Waf1 through stabilization of p53. Although ZBP-89 binds mutant and wild-type p53, only wild-type p53 is stabilized. Moreover, mutant p53 shifts the subnuclear location of ZBP-89 to the nuclear periphery, which is a domain rich in heterochromatin. This finding led to the conclusion that mutant p53 exerts a dominant negative effect on ZBP-89. We propose that gene silencing by mutant p53 might be mediated by sequestering ZBP-89 within heterochromatin regions at the nuclear periphery. Overall, ZBP-89 is a butyrate-regulated coactivator of p53 and is able to induce p21Waf1 gene expression through both p53-dependent and -independent mechanisms to inhibit cell growth.

KEY WORDS: • p53 • p21Waf1 • zinc finger • apoptosis • p300 • heterochromatin

Colorectal cancer is the second leading cause of cancer death in the U.S. ( 1). Fortunately, the disease is treatable and preventable ( 2). Epidemiologic studies indicate that a diet high in fiber is protective against colon cancer ( 3). The short-chain fatty acid butyrate is one of several fiber-derived fermentation products that is capable of maintaining epithelial cell differentiation ( 4). The differentiation effects were initially revealed after treatment of erythroleukemic cells with butyrate ( 5). Subsequently, it was discovered that induction of differentiation by butyrate correlates with histone hyperacetylation ( 6– 8) due to suppression of histone deacetylases [HDAC,4 ( 9– 13)]. Thus, the histone hyperacetylating effects of butyrate may in fact be one mechanism by which dietary fiber exerts its anticancer effects ( 14). Recent reviews recommend butyrate as a potent anticancer agent ( 15– 17). Collectively, early studies emphasized the global effects of butyrate on chromatin remodeling but provided little explanation of how the effects of butyrate are directed to a specific gene target. More recently, butyrate was implicated in the regulation of specific genes. Both globin and the cyclin-dependent kinase inhibitor p21Waf1 are transcriptional targets regulated by butyrate ( 18, 19).

The molecular basis for the gene-specific effects of butyrate remains poorly defined. In addition to histone acetylation, it is now known that DNA-binding proteins can become acetylated ( 20). The proposed function of acetylated transcription factors varies and includes increased or decreased DNA binding as well as protein stability ( 21). In many instances, the genetic targets of butyrate are GC-rich sequences that bind Sp1 and Sp3. {gamma}-Transferase ( 22), insulin-like growth factor binding protein-3 ( 23), G{alpha}i2 ( 24), galectin ( 25), Cox-1 ( 26) and intestinal alkaline phosphatase ( 27) are all upregulated by butyrate through Sp1 sites. Sp1-binding sites also are implicated in the butyrate induction of p21Waf1 gene expression ( 28). Recruitment of the histone acetyltransferase (HAT) p300 cooperates with Sp1 and Sp3 to mediate the effects of butyrate to this promoter ( 29). However, Sp1 does not complex with p300 but instead binds HDAC1 ( 30, 31). The Sp1-HDAC1 complex in turn forms complexes with other corepressors such as Sin3A ( 32). Thus, Sp1 appears to be the factor that confers promoter repression by recruiting HDAC and corepressor complexes.

Recently, it was suggested that Sp3 mediates promoter activation in the presence of HDAC inhibitors ( 33). Sp3 is highly acetylated in vivo, and its acetylation contributes to its transcriptional activity ( 34). Moreover, p300 was recently found to interact with Sp3 ( 35). Together these studies suggest that Sp1 and Sp3 cooperatively transduce butyrate regulation to specific promoters through GC-rich sites and differential recruitment of corepressors and coactivators. Nevertheless, due to the promiscuous interactions of the Sp1 transcription factor family with other proteins such as c-Jun and Egr-1, additional DNA-binding proteins likely play a role in butyrate regulation ( 31, 36). Moreover, zinc-finger binding protein-89 (ZBP-89) is another DNA-binding protein that binds GC-rich sites and mediates butyrate gene expression ( 37). Understanding the mechanisms by which butyrate suppresses growth through ZBP-89 is the focus of this review.

ZBP-89 structure

ZBP-89 (also known as ZNF-148, Zfp-148, BFCOL1 and BERF-1) is a Krüppel-type zinc-finger protein that is composed of 794 residues. It was cloned by the screening of an expression library with a GC-rich epidermal growth factor–responsive element from the gastrin promoter ( 38). ZBP-89 also binds similar DNA elements within several other promoters ( 39– 45). The protein ht-ß is smaller than ZBP-89 but is identical to the first 454 amino acids in ZBP-89 except that it lacks the C-terminal 340 residues ( 46). The four Krüppel-type zinc fingers reside within the N-terminus of the protein. In addition to its proximal zinc-finger domain, there is a glutamic acid–rich domain within the first 100 residues of the protein that is followed by basic domains that flank the zinc-finger DNA-binding region ( Fig. 1). The distal 250 residues consist of a third basic domain plus serine-rich and PEST (proline, glutamic acid, serine, threonine) domains, which suggests that ZBP-89 might undergo proteolytic degradation or processing. However, a recent study indicates that the multiple ZBP-89 species that are observed on immunoblot also may represent alternative splice forms ( 47). Although ubiquitous, a higher level of ZBP-89 protein is expressed in T cells ( 42, 45, 48). Several expressed-sequence tags derived from human tissues confirm the presence of ZBP-89 in normal human islets and insulinomas as well as rat pancreatic islets, which suggests preferred expression in the endocrine pancreas ( 49). The full-length protein functions as a repressor of gastrin gene expression and other growth-factor–regulated genes such as ornithine decarboxylase [ODC, ( 38, 49)]. Another member of the ZBP family was cloned and designated ZBP-99 on the basis of a homologous zinc-finger domain and a greater molecular weight ( 50, 51). Thus, the ZBP proteins are a family of N-terminal zinc-finger transcriptional regulators, which is in contrast to the Sp1 family, whose zinc-finger domain resides in the extreme C-terminus of the protein ( 52). ZBP-89 has bifunctional regulatory domains, which suggests that it may function as a transcriptional activator and repressor ( 39, 40). Consistent with its ability to repress the gastrin and ODC genes (both of which stimulate proliferation), ZBP-89 inhibits cell growth ( 53). Subsequently, we found that ZBP-89 regulates growth in part by stimulating the cyclin-dependent kinase inhibitor p21Waf1 in a butyrate-dependent manner through recruitment of the HAT p300 ( 37). ZBP-89 triggers growth arrest in a p53-dependent manner by preventing the nuclear export of p53 ( 54). Moreover, the protein also induces apoptosis through a p53-independent mechanism ( 54).



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  		FIGURE 1  Structure of zinc-finger binding protein-89 (ZBP-89). The structural domains of ZBP-89 include the acidic domain (amino acids 54–99), basic domains (amino acids 129–153, 313–335 and 470–485), four C2H2 zinc fingers (amino acids 173–278), a serine-rich domain (amino acids 569–596) and a PEST domain (proline, glutamic acid, serine and threonine; amino acids 569–596). The C-terminus of ZBP-89 contains a transactivation domain ( 39, 40). Domains that interact (ID) with p53 and p300 are indicated ( 37, 54).

 
Published reports indicate that ZBP-89 is able to both stimulate and repress gene expression ( 38, 41, 46, 48), yet the overall effect of ectopic ZBP-89 expression is growth suppression ( 53). Therefore, to better understand how ZPB-89 regulates cell growth, we sought to identify the signals that stimulate ZBP-89 gene expression and induce growth arrest. Several extracellular signals were found to fit these criteria. Retinoic acid suppresses ODC and tumor growth in part through an increase in ZBP-89 ( 55). In cultured cells, serum starvation stimulates ZBP-89 gene expression that correlates with growth arrest ( 54). Butyrate treatment of human colon cell lines stimulates maximal ZBP-89 gene expression within 3–5 d ( 37). Thus, the relatively slow activation of ZBP-89 gene expression by butyrate suggests that this fatty acid may cooperate with ZBP-89 to inhibit cell growth by mechanisms other than the simple increase of ZBP-89 protein levels.

ZBP-89 regulation of growth arrest through p21Waf1

Recalling that butyrate modulates gene expression through its ability to increase histone acetylation and subsequent chromatin remodeling, we focused our efforts on posttranslational mechanisms that might regulate ZBP-89 activity. Millimolar concentrations of butyrate are produced in the human colon by endogenous intestinal bacteria during the fermentation of dietary fiber. Butyrate maintains the healthy differentiated state of normal colonic epithelial cells, inhibits cell growth and promotes differentiation of neoplastic cells ( 56). Moreover, butyrate is known to induce apoptosis in a number of cancer cell types including colon cell lines ( 57– 59). The p21Waf1 gene is an essential inhibitor of cell growth and is required for butyrate-mediated growth inhibition in HT-29 colon cells ( 19). Regulation of the p21Waf1 promoter is mediated through its proximal GC-rich elements that bind Sp1 and other zinc-finger factors ( 60). Therefore, we reasoned that ZBP-89, by recognizing GC-rich sequences, also might mediate butyrate inhibition of cell growth through these same Sp1 elements within the p21Waf1 promoter. Indeed, ZBP-89 is capable of binding to proximal GC-rich elements within the human p21Waf1 promoter ( 37, 61). Furthermore, analysis of the butyrate response in HT-29 cells reveals that ZBP-89 binding is not induced during the first 2 h of treatment when p21Waf1 induction is maximal. Rather, ZBP-89 potentiation of butyrate-activated p21Waf1 gene expression is due to recruitment of the coactivator p300 ( 37). Inhibition of HDAC by butyrate allows acetylation to occur at promoter sites where HAT (e.g., p300) have been recruited ( Fig. 2). In particular, ZBP-89 appears to be essential to the recruitment of p300 to the p21Waf1 promoter ( 37). Butyrate treatment of HT-29 cells induces their growth arrest and differentiation into alkaline phosphatase–expressing small intestine-like cells by day 3 ( 56). Collectively, these studies suggest that ZBP-89 induction of the p21Waf1 promoter in the presence of butyrate is an early event (<6 h) that culminates in growth arrest. These early events do not correlate with increased levels or binding of ZBP-89, which implicates cooperation of posttranslational mechanisms to stimulate p21Waf1 gene expression. Subsequently, the delayed effects (i.e., differentiation) of butyrate (>48 h) correlate with elevated levels of ZBP-89 that in turn must regulate other late-responding transcriptional targets that are yet to be determined.



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  		FIGURE 2  Model for ZBP-89 activation of p21Waf1 in the presence of butyrate. Sp1 is known to bind histone deacetylase (HDAC)1. Recently, we showed that ZBP-89 recruits p300 to the p21Waf1 promoter. We propose that promoter activation may occur by inhibition of HDAC activity. In this way, the HDAC activity present in the p300 coactivator predominates and thereby permits local increased acetylase activity. TSA, trichostatin. [Adapted from Bai and Merchant ( 37) with permission.]

 
ZBP-89 regulation of growth arrest through p53

The initial studies of ZBP-89 regulation of the p21Waf1 promoter were conducted on the HT-29 colon cancer line in which the p53 tumor suppressor gene was mutated and transcriptional activation was prevented. Because p53 also mediates growth arrest through activation of the p21Waf1 promoter, we examined the effects of ZBP-89 on proliferation in cell lines that contain wild-type p53. In this study, we found that overexpression of ZBP-89 inhibits cell growth while increasing the expression of both p53 and p21Waf1 ( 54). Because p53 binds the p21Waf1 promoter directly, we reasoned that ZBP-89 might regulate growth arrest by increasing the cellular levels of p53 and subsequently transactivating p21Waf1. The results of our study reveal that ZBP-89 does not increase p53 gene expression, but instead directly binds and stabilizes p53 protein ( 37). The interaction occurs between the zinc-finger domain of ZBP-89 and the DNA-binding/C-terminal domains of p53. ZBP-89 blocks the shuttling of p53 to the cytoplasm, where it is normally degraded by the proteosome ( Fig. 3). This result effectively prolongs the half-life of p53 by retaining it in the nucleus. Therefore, ZBP-89 activates p21Waf1 gene expression and growth arrest by both p53-dependent and -independent mechanisms. Moreover, these studies reveal that growth inhibition by ZBP-89 might occur by either protein-protein interactions or direct DNA binding.



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  		FIGURE 3  Model for ZBP-89 stabilization of p53. ZBP-89 increases the protein levels of p53 exclusive of Mdm2 or p14ARF. The zinc-finger domain of ZBP-89 interacts with the DNA-binding and C-terminal domains of p53 to retard its translocation to the cytoplasm, where it is normally degraded by the proteasome. Numbered p53 domains are highly conserved. The DNA binding region is indicated between residues 117 and 286. The Mdm2-interacting domain is located between residues 26 and 37.

 
ZBP-89 potentiation of p21Waf1 promoter activation by butyrate was initially conducted in the HT-29 colon cell line that contains nonfunctional mutant p53. Because p21Waf1 is a major direct transcriptional target of p53 ( 62), and because ZBP-89 binds to and stabilizes wild-type p53, we queried whether ZBP-89 also might increase mutant p53 levels and account for the increased mutant p53 levels in some colorectal cancers. In fact, ZBP-89 expression is elevated in gastric cancer ( 63). Indeed, ZBP-89 is able to bind mutant p53 but does not increase its cellular level ( 54). In addition, ectopic expression of ZBP-89 alone in the absence of butyrate has no effect on the transcriptional activation of p53-dependent genes ( 54). Therefore, we conclude that the increase in mutant p53 levels in gastrointestinal cancers is not due to interaction with ZBP-89. Recently, we analyzed additional p53 mutants within the DNA-binding domain and found that none of the mutants are stabilized by ZBP-89 (M. Okada and J. L. Merchant, unpublished observations). Because ZBP-89 does not overcome the repressive effects of mutant p53, we explored the possibility that mutant p53 might exert transcriptional repression by altering the subnuclear localization of ZBP-89.

A consistent finding when ZBP-89 was coexpressed with transcriptionally inactive p53 mutants was that both proteins colocalize to the nuclear periphery (M. Okada and J. L. Merchant, unpublished observations). The perinuclear subdomain contains a nuclear envelope that is associated with heterochromatin and usually lacks transcriptional activity ( 64). Thus, we hypothesized that sequestration of ZBP-89 to this region is a possible mechanism by which p53 mutants can silence p53-dependent genes. Indeed, biochemical fractionation of the soluble nuclear fraction from nuclear scaffold reveals the presence of more ZBP-89 protein in the nuclear scaffold fraction (J. L. Merchant & M. Okada, unpublished data).

These initial results raise the possibility that the fate of nuclear ZBP-89 might be altered by butyrate treatment to activate gene expression. If butyrate does indeed alter the activity of ZBP-89 in the presence of mutant p53, then this result would suggest that it is possible that histone acetylation as well as ZBP-89 acetylation is sufficient to overcome the inhibitory effect of mutant p53 on the p21Waf1 promoter. Thus, potentiation of butyrate induction might occur because ZBP-89 is able to direct histone acetylation and subsequently transcriptional activation to the promoters that it binds ( Fig. 4). In the case of the p21Waf1 promoter, ZBP-89 is able to recruit p300 HAT activity and bind to the p21Waf1 promoter directly as well as activate the promoter through stabilization of p53. It is known from chromatin immunoprecipitation (ChIP) and microarray analysis that the major transcriptional target of p53 is p21Waf1 ( 62, 65). Therefore, increasing p53 levels should be sufficient to stimulate p21Waf1. Taken together, ZBP-89 regulates the p21Waf1 promoter by two mechanisms: stabilization then increased binding of p53 and/or direct ZBP-89 binding to the p21Waf1 promoter, following butyrate-dependent activation.



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  		FIGURE 4  Proposed mechanism of mutant p53 gene silencing. The nuclear periphery is one of several nuclear domains rich in heterochromatin that in turn mediates gene silencing. Mutant p53 sequesters ZBP-89 to the nuclear periphery. Thus, mutant p53 has a dominant negative effect on ZBP-89 and subsequently its target genes, perhaps through its ability to alter ZBP-89 subnuclear location. We propose that butyrate may overcome p53 gene silencing at the p21Waf1 promoter by inhibiting HDAC. Local acetyltransferase activity increases within the proximal p21Waf1 promoter because ZBP-89 is able to recruit p300 (a histone acetyltransferase). Chromatin structure is modified in response to elevated acetyltransferase activity, which thereby permits activation of the p21Waf1 promoter to proceed. Whether acetylation of both ZBP-89 and p53 is required for optimal activation is the focus of future studies.

 
Future directions

Questions that remain unanswered are whether butyrate modulates ZBP-89 subnuclear localization, whether direct acetylation of ZBP-89 or p53 affects transactivation and whether butyrate modulates ZBP-89 functions as an activator or repressor. Also, it is still unclear why ZBP-89, like mutant p53, is elevated in some cancers. It is hoped that by studying this relatively novel and complex transcriptional regulator we will further our understanding of how butyrate targets specific genes and modulates epithelial cell growth. Certainly, other putative "Sp1 sites" that mediate butyrate responsiveness within other genes should be reexamined in light of the role of ZBP-89 on the p21Waf1 promoter.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the "Nutritional Genomics and Proteomics in Cancer Prevention Conference" held September 5–6, 2002, in Bethesda, MD. This meeting was sponsored by the Center for Cancer Research, National Cancer Institute; Division of Cancer Prevention, National Cancer Institute; National Center for Complementary and Alternative Medicine, National Institutes of Health; Office of Dietary Supplements, National Institutes of Health; Office of Rare Diseases, National Institutes of Health; and the American Society for Nutritional Sciences. Guest editors for the supplement were Young S. Kim and John A. Milner, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD. Back

2 This work was supported by Public Health Service National Institutes of Health grant DK-55732 (to J. L. Merchant) and the Robert and Sally Funderburg Award from the American Digestive Health Foundation. Back

4 Abbreviations used: HAT, histone acetyltransferase; HDAC, histone deacetylase; ODC, orinithine decarboxylase; ZBP-89, zinc-finger binding protein-89. Back


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