A Transcriptional Regulatory Role of the THAP11-HCF-1 Complex in Colon Cancer Cell Function

Division of Reproductive Biology Research, Department of OB/GYN, Northwestern University, Chicago, Illinois, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2012; 32(9):1654-70. DOI: 10.1128/MCB.06033-11
Source: PubMed


The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that
THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP
proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional
regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased
THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant
decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80
differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically
with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated
gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively,
these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest
that the THAP11–HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer.

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Available from: Jian-Jun Wei
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    • "However, immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in colon cancer cells resulted in a significant decrease in cell proliferation and THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters, then mediating transcriptional regulation [7]. These data suggest that THAP11 is a an important transcriptional and cell growth regulator. "
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    ABSTRACT: Hematopoiesis is a complex process regulated by sets of transcription factors in a stage-specific and context-dependent manner. THAP11 is a transcription factor involved in cell growth, ES cell pluripotency, and embryogenesis. Here we showed that THAP11 was down-regulated during erythroid differentiation but up-regulated during megakaryocytic differentiation of cord blood CD34+ cells. Overexpression of THAP11 in K562 cells inhibited the erythroid differentiation induced by hemin with decreased numbers of benzidine-positive cells and decreased mRNA levels of α-globin (HBA) and glycophorin A (GPA), and knockdown of THAP11 enhanced the erythroid differentiation. Conversely, THAP11 overexpression accelerated the megakaryocytic differentiation induced by phorbol myristate acetate (PMA) with increased percentage of CD41+ cells, increased numbers of 4N cells, and elevated CD61 mRNA levels, and THAP11 knockdown attenuated the megakaryocytic differentiation. The expression levels of transcription factors such as c-Myc, c-Myb, GATA-2, and Fli1 were changed by THAP11 overexpression. In this way, our results suggested that THAP11 reversibly regulated erythroid and megakaryocytic differentiation.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Until recently, it was admitted that THAP11 had a repressor function mediated by its co-factor HCF-1 (27). However, it was recently shown that for some genes, THAP11/HCF1 could act as a transcription activator as well (25,26). In mouse, Ronin (THAP11 orthologue) is essential for embryogenesis and the pluripotency of embryonic stem cells (mES cells) (27). "
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    ABSTRACT: ZNF143 is a zinc-finger protein involved in the transcriptional regulation of both coding and non-coding genes from polymerase II and III promoters. Our study deciphers the genome-wide regulatory role of ZNF143 in relation with the two previously unrelated transcription factors Notch1/ICN1 and thanatos-associated protein 11 (THAP11) in several human and murine cells. We show that two distinct motifs, SBS1 and SBS2, are associated to ZNF143-binding events in promoters of >3000 genes. Without co-occupation, these sites are also bound by Notch1/ICN1 in T-lymphoblastic leukaemia cells as well as by THAP11, a factor involved in self-renewal of embryonic stem cells. We present evidence that ICN1 binding overlaps with ZNF143 binding events at the SBS1 and SBS2 motifs, whereas the overlap occurs only at SBS2 for THAP11. We demonstrate that the three factors modulate expression of common target genes through the mutually exclusive occupation of overlapping binding sites. The model we propose predicts that the binding competition between the three factors controls biological processes such as rapid cell growth of both neoplastic and stem cells. Overall, our study establishes a novel relationship between ZNF143, THAP11 and ICN1 and reveals important insights into ZNF143-mediated gene regulation.
    Full-text · Article · Feb 2013 · Nucleic Acids Research
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    • "In THAP11, the length of the loop is significantly shortened, the arginine residue (Arg70, numbering corresponding to THAP11) present in the loop is way too far from the consensus thymine (more than 10 A ˚ ), precluding DNA minor groove recognition, at least using this thymine as a specific recognition site and a canonical, straight, B-DNA conformation. Nevertheless, THAP11 and its murine homolog have been claimed to recognize specific DNA targets and subsequently collaborate with interaction partners to achieve a specific regulatory response (Parker et al. 2012; Zhu et al. 2009). Two DNA consensus sequences (Ronin-binding sequence and Ronin-binding motif) distinct from the THABS motif were identified (Fig. 3a–b). "
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    ABSTRACT: The THAP (THanatos-Associated Protein) domain is an evolutionary conserved C2CH zinc-coordinating domain shared with a large family of cellular factors (THAP proteins). Many members of the THAP family act as transcription factors that control cell proliferation, cell cycle progression, angiogenesis, apoptosis and epigenetic gene silencing. They recognize specific DNA sequences in the promoters of target genes and subsequently recruit effector proteins. Recent structural and functional studies have allowed getting better insight into the nuclear and cellular functions of some THAP members and the molecular mechanisms by which they recognize DNA. The present article reviews recent advances in the knowledge of the THAP domains structures and their interaction with DNA, with a particular focus on NMR. It provides the solution structure of the THAP domain of THAP11, a recently characterized human THAP protein with important functions in transcription and cell growth in colon cancer.
    Full-text · Article · Jan 2013 · Journal of Biomolecular NMR
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