Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc

Abstract

Thanatos-associated proteins (THAPs) are zinc-dependent, sequence-specific DNA-binding factors involved in cell proliferation, apoptosis, cell cycle, chromatin modification and transcriptional regulation. THAP11 is the most recently described member of this human protein family. In this study, we show that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several human tumor tissues. Overexpression of THAP11 markedly inhibits growth of a number of different cells, including cancer cells and non-transformed cells. Silencing of THAP11 by RNA interference in HepG2 cells results in loss of cell growth repression. These results suggest that human THAP11 may be an endogenous physiologic regulator of cell proliferation. We also provide evidence that the function of THAP11 is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent c-Myc transcriptional repression. Chromatin immunoprecipitations and EMSA assay suggest that THAP11 directly binds to the c-Myc promoter. The findings that expression of c-Myc rescues significantly cells from THAP11-mediated cell growth suppression and that THAP11 expression only slightly inhibits c-Myc null fibroblasts cells growth reveal that THAP11 inhibits cell growth through downregulation of c-Myc expression. Taken together, these suggest that THAP11 functions as a cell growth suppressor by negatively regulating the expression of c-Myc. Cell Death and Differentiation (2009) 16, 395-405; doi:10.1038/cdd.2008 published online 14 November 2008 The THAP proteins (Thanatos-associated protein), a novel family of cellular factors, are characterized by the presence of an evolutionarily conserved protein motif. The motif designated as the THAP domain presents striking similarities with the site-specific DNA-binding domain of Drosophila P element transposase.

THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death

“…Previous studies have shown two members of the same family, THAP1 and THAP11, can regulate cell proliferation (6,52). Furthermore, genetic studies using C. elegans support a role of THAP proteins in cell cycle regulation.…”

“…THAP5 has an atypical zinc finger domain at its amino terminus that could bind to specific DNA sequences on different promoters. A recent study showed that another member of the same family, THAP11, could inhibit cell cycle by binding to the promoter of c-Myc and downregulating its expression (52).…”

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

“…Individual THAP proteins have been implicated in a diverse array of physiological processes, including cell proliferation, regulation of transcription, apoptosis, and maintenance of embryonic stem (ES) cell pluripotency (2,3,6,9,12,24,33,45). The DNA-and HCF-1-binding properties of THAP proteins naturally suggest that these proteins may regulate normal or disease-specific physiological processes in a DNA-and chromatin-dependent manner.…”

“…The majority of conserved THAP proteins also contain a coiled-coil protein interaction domain adjacent to a host cell factor 1 (HCF-1)-binding motif (HBM) (26). The tetrapeptide HBM (E/DHXY, where X is any amino acid) facilitates the interaction of THAP proteins and other DNA-binding factors with the Kelch domain of HCF-1, a transcriptional coregulator and cell proliferation factor associated with a variety of enzymatic and histone-modifying activities, including SIN3/HDAC histone deacetylase, SET1/MLL histone methyltransferase, and MOF histone acetyltransferase (11,22,23,26,30,39,42).Individual THAP proteins have been implicated in a diverse array of physiological processes, including cell proliferation, regulation of transcription, apoptosis, and maintenance of embryonic stem (ES) cell pluripotency (2,3,6,9,12,24,33,45). The DNA-and HCF-1-binding properties of THAP proteins naturally suggest that these proteins may regulate normal or disease-specific physiological processes in a DNA-and chromatin-dependent manner.…”

The potential role of O-GlcNAc modification in cancer epigenetics

“…Twelve THAP proteins have been identified in humans (THAP0 to THAP11). Individual THAP proteins are involved in different physiological processes, including cell Brought to you by | MIT Libraries Authenticated Download Date | 5/11/18 7:43 PM proliferation, regulation of transcription, apoptosis, and the maintenance of embryonic stem cell pluripotency [96][97][98][99][100]. THAP proteins in association with HCF-1 may function in chromatin-dependent processes, and aberrant regulation of these proteins may be involved in many diseases, including cancer.…”