Histone Deacetylase 7 Promotes PML Sumoylation and Is Essential for PML Nuclear Body Formation

Gao, Chengzhuo; Ho, Chun Chen; Reineke, Erin L.; Lam, Minh; Cheng, Xiangguo; Stanya, Kristopher J.; Liu, Yu; Chakraborty, Sharmistha; Shih, Hsiu Ming; Kao, Hung Ying

doi:10.1128/mcb.00874-08

Cited by 67 publications

(65 citation statements)

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“…The deacetylase activity in HDAC7 is known to be relatively weak (61), and it is therefore likely that the protein has additional enzymatic and/or nonenzymatic functions critical in repression, which are yet to be discovered. One possibility is that its recently described Sumo E3 ligase activity (18,23) might play a role in ER␣ given that posttranslational modification by sumoylation is primarily associated with transcriptional repression (48). Future studies will address this question by testing whether HDAC7 can mediate sumoylation of ER␣, which has previously been shown to be sumoylated (62,71).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM

Malik

Jiang

Garee

et al. 2010

Molecular and Cellular Biology

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Activation of estrogen receptor ␣ (ER␣) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ER␣-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ER␣, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ER␣ and represses ER␣'s transcriptional activity-this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes.

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM

Malik

Jiang

Garee

et al. 2010

Molecular and Cellular Biology

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“…Thus, class I HDACs interact with PML and this interaction is required for the transcriptional repression function of PML. 39,40 In addition, class IIa HDACs -HDAC4, HDAC5, and HDAC7 -increase PML sumoylation in an acetylationindependent manner, 41 and although it is not clear exactly how HDAC4 and related members positively regulate the sumoylation levels of PML, a putative SUMO E3 ligase activity has been suggested. 42 PML has an inhibitory effect on virus infections in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 stabilizes PML promoting its sumoylation

et al. 2010

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SIRT1, the closest mammalian homolog of yeast Sir2, is an NAD þ -dependent deacetylase with relevant functions in cancer, aging, and metabolism among other processes. SIRT1 has a diffuse nuclear localization but is recruited to the PML nuclear bodies (PML-NBs) after PML upregulation. However, the functions of SIRT1 in the PML-NBs are unknown. In this study we show that primary mouse embryo fibroblasts lacking SIRT1 contain reduced PML protein levels that are increased after reintroduction of SIRT1. In addition, overexpression of SIRT1 in HEK-293 cells increases the amount of PML protein whereas knockdown of SIRT1 reduces the size and number of PML-NBs and the levels of PML protein in HeLa cells. SIRT1 stimulates PML sumoylation in vitro and in vivo in a deacetylase-independent manner. Importantly, the absence of SIRT1 reduces the apoptotic response of vesicular stomatitis virus-infected cells and favors the extent of this PML-sensitive virus replication. These results show a novel function of SIRT1 in the control of PML and PML-NBs. The tumor suppressor PML is the main and essential component of the nuclear bodies (NBs), the dynamic compartments that participate in a number of cellular processes, including apoptosis, transcriptional regulation, DNA repair, and protection against viral infection. 1,2 PML acts as a tumor suppressor, antagonizing initiation, promotion, and progression of tumors of various histological origins. 3 PML is also implicated in the regulation of infection by a variety of RNA viruses, adenoviruses, and human cytomegalovirus. 4-7 Its function is regulated by post-translational modifications such as phosphorylation, sumoylation, ubiquitination, and acetylation. However, only the sumoylation of PML has been shown as essential for the formation of the PML-NBs and a crucial process for PML-dependent apoptosis and transcriptional regulation. 8 In addition to PML, PML-NBs contain several other proteins, such as SP100, SUMO-1, pRB, p53, and lately, the NAD þ -dependent, type III, histone/protein deacetylase SIRT1. 9,10 SIRT1 is the best-characterized class III histone deacetylase in mammalian cells and the closest homolog to yeast Sir2. However, although most of SIRT1 functions are related to its enzymatic activity, deacetylation-independent activities of SIRT1 have also been proposed. 11-14 SIRT1 is involved in a wide spectrum of biological processes through diverse substrates such as the tumor suppressor p53, 9,15-17 the transcription factor NF-kB, 18 and the FOXO family of transcription factors. 12,14,19,20 Although SIRT1 has a diffuse nuclear localization, it is recruited to the PML-NBs after PML upregulation. However, the functional significance of this PML-SIRT1 interaction has not been addressed.In this report, we show that there is a correlation between the levels of SIRT1 and PML present in both primary and transfected cells. This positive regulation of PML levels by SIRT1 is mediated by an increase in the sumoylation of PML by SIRT1, in a deacetylation-independent manner. Functional sign...

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“…In vitro deacetylation assays also demonstrated that class IIa HDACs possess potent deacetylase activity (31). Recently, we along with other labs have demonstrated that class IIa HDACs, including HDAC4 and HDAC7, are able to potentiate sumoylation of a variety of proteins including PML, LXR, MEF2, and HIC1 (19,25,(32)(33)(34). In this study, we show for the first time that HDAC7 binds FLNB in a ubiquitination-dependent manner.…”

Section: Discussionmentioning

confidence: 61%

“…Expression plasmids for hemagglutinin (HA)-HDAC5 and -HDAC7, constitutively active CaMK I, green fluorescent protein (GFP)-HDAC7, glutathione S-transferase (GST)-HDAC7, HAubiquitin (Ub), FLAG-Ub, and the myocyte enhancer factor 2 (MEF2)-driven reporter construct have been previously described (19)(20)(21). HDAC7 constructs were generated from mouse cDNA.…”

Section: Methodsmentioning

confidence: 99%