Transcriptional Regulation of the Transforming Growth Factor β Type II Receptor Gene by Histone Acetyltransferase and Deacetylase Is Mediated by NF-Y in Human Breast Cancer Cells

Park, Seok Hee; Lee, Sae Ra; Kim, Byung Chul; Cho, Eun Ah; Patel, Sejal P.; Kang, Hee-Bum; Sausville, Edward A.; Nakanishi, Osamu; Trepel, Jane B.; Lee, Byoung Ick; Kim, Seong‐Jin

doi:10.1074/jbc.m106451200

Cited by 77 publications

(64 citation statements)

References 31 publications

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“…The p300 and Sp1 association was also shown to contribute to Sp1-dependent p21 promoter activity (24). PCAF and NF-Y association was reported to activate RII promoter activity (27). However, how the co-activator/acetyltransferase interacts with DNA-binding activators to modulate their actions in the context of promoter access is not completely understood.…”

Section: Figmentioning

confidence: 99%

Restoration of Transforming Growth Factor-β Signaling through Receptor RI Induction by Histone Deacetylase Activity Inhibition in Breast Cancer Cells

Ammanamanchi

Brattain

2004

Journal of Biological Chemistry

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The loss of transforming growth factor-␤ (TGF-␤) response due to the dysregulation of TGF-␤ receptors type I (RI) and type II (RII) is well known for its contribution to oncogenesis. Estrogen receptor-expressing breast cancer cells are refractory to TGF-␤-mediated growth control because of the reduced expression of TGF-␤ receptors. Although RII is required for the binding of TGF-␤ to RI, RI is responsible for directly transducing TGF-␤ signals through the Smad protein family. Treatment of estrogen receptor-expressing MCF-7L and ZR75 breast cancer cells with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) led to a dramatic induction of RI. Accumulation of acetylated histones H3 and H4 was observed in the SAHAtreated cells. Chromatin immunoprecipitation analysis followed by PCR with RI promoter-specific primers indicated an accumulation of acetylated histones in chromatin associated with the RI gene, suggesting that histone deacetylation was involved in the transcriptional inactivation of RI. SAHA treatment stimulated RI promoter activity through the inhibition of Sp1/Sp3-associated HDAC activity. Histone acetyltransferase p300 stimulated RI promoter activity, thus further confirming the involvement of HDAC activity in the transcriptional repression of RI. Significantly, SAHA-mediated RI regeneration restored the TGF-␤ response in breast cancer cells.Transforming growth factor-␤ (TGF-␤), 1 a 25-kDa homodimeric polypeptide, plays an important role in the growth inhibition of most normal epithelial and some cancer cells (1). TGF-␤ functions through cell surface receptors referred to as type I (RI) and type II (RII). RI requires RII for the binding of TGF-␤. However, RI is a direct player in the TGF-␤ signaling pathway as it conveys signals from TGF-␤ through the activation of Smad protein family members (2). The loss of TGF-␤ response is well known for its contribution to oncogenesis and tumor progression. Direct involvement of RI in TGF-␤ signal transduction would suggest that loss or reduced expression of RI could contribute to TGF-␤ resistance resulting in a growth advantage that contributes to tumor progression.TGF-␤ resistance due to methylation of the RI promoter or RI promoter repression by Sp1 deficiency was reported to be a cause of TGF-␤ resistance in gastric and colon carcinomas (3,4). The RI gene is frequently mutated in ovarian carcinomas (5). Decreased expression of RI is associated with poor prognosis in bladder transitional cell carcinomas (6). Reduced RI expression is also associated with unfavorable prognosis in esophageal squamous cell carcinoma (7). RI*6A, a polymorphic allele of RI, is emerging as a high frequency, low penetrance tumor susceptibility allele that predisposes to the development of breast, ovarian, and colorectal cancer, as well as hematologic malignancies (8). Polymorphisms in the microsatellite region of the RI gene were reported in head and neck cancers as well as non-small cell lung cancer (9, 10). Mutations in the kinase domain of the RI gene we...

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Section: Figmentioning

confidence: 99%

Restoration of Transforming Growth Factor-β Signaling through Receptor RI Induction by Histone Deacetylase Activity Inhibition in Breast Cancer Cells

Ammanamanchi

Brattain

2004

Journal of Biological Chemistry

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“…An important level of regulation links acetylation levels and NF-Y activity. Functionally, inhibition of HDAC's activity by trichostatin A (TSA) treatment leads to 1) activation of the MDR1 (multidrug resistance promoter; Jin and Scotto, 1998); 2) a dramatic increase in the activity of TGF-␤ II receptor promoter (Park et al, 2002); and 3) activation of the HSP70 promoter in the absence of heat shock in Xenopus oocytes (Li et al, 1998). All these effects are strictly dependent on the presence of the CCAAT boxes.…”

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confidence: 99%

Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

Manni¹,

Caretti

Artuso³

et al. 2008

MBoC

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Here we show that the levels of NF-YA protein are regulated posttranslationally by ubiquitylation and acetylation. A NF-YA protein carrying four mutated lysines in the C-terminal domain is more stable than the wild-type form, indicating that these lysines are ubiquitylated Two of the lysines are acetylated in vitro by p300, suggesting a competition between ubiquitylation and acetylation of overlapping residues. Interestingly, overexpression of a degradation-resistant NF-YA protein leads to sustained expression of mitotic cyclin complexes and increased cell proliferation, indicating that a tight regulation of NF-YA levels contributes to regulate NF-Y activity. INTRODUCTIONThe CCAAT-binding transcription factor NF-Y is a heteromeric protein composed of three subunits, NF-YA, -YB, and -YC, all necessary for CCAAT binding (Mantovani, 1999). The NF-Y complex supports the basal transcription of a class of regulatory genes responsible for cell cycle progression, among which are mitotic cyclin complexes (Zwicker et al., 1995a,b;Bolognese et al., 1999;Farina et al., 1999;Korner et al., 2001;Gurtner et al., 2003Gurtner et al., , 2008Di Agostino et al., 2006). Knock-out mice clearly demonstrates that NF-Y dependent transcription is essential during early mouse development (Bhattacharya et al., 2003). The NF-Y function in proliferation is also demonstrated by the inhibition of DNA binding by endogenous NF-Y, resulting in retardation of fibroblast growth, which is brought about by overexpression of a dominant negative mutant of the NF-YA subunit (Hu and Maity, 2000). The differential expression of NF-YA, altering NF-Y CCAAT-binding activity, has been observed in several cell lines and tissues both during cell cycle progression and under specific conditions. NF-YA expression is modulated during the cell cycle, being high in G1, further increasing in S, and then decreasing in the G2/M phase (Bolognese et al., 1999). Reduction of NF-YA expression has been reported in IMR-90 fibroblasts after serum deprivation (Chang et al., 1994) and in human monocytes (Marziali et al., 1997). The NF-YA protein is not expressed in terminally differentiated C2C12 muscle cells and adult skeletal muscle tissues (Farina et al., 1999;Gurtner et al., 2003Gurtner et al., , 2008. These observations show that levels of NF-YA dictate the function of the NF-Y complex. Interestingly, control of NF-YA accumulation is posttranscriptional, because NF-YA mRNA is relatively constant in growing and differentiated cells (Bolognese et al., 1999;Farina et al., 1999). Yet, the mechanisms regulating the stability of the NF-YA protein remain unknown.The covalent addition of ubiquitin, a 76-amino acid protein highly conserved among eukaryotes, is an increasingly common posttranslation modification that controls both the expression and the activity of numerous proteins in the eukaryotic cell (Hershko and Ciechanover, 1998;Ciechanover et al., 2000). The ubiquitin-proteasome pathway is composed of the ubiquitin-conjugating system and the 26S proteasome; the latter contain...

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“…Role of co-repressors and co-activators in the regulation of the murine GADD45g promoter NF-Y and Oct-1 can interact with HAT-containing coactivator complexes and HDAC-containing co-repressor complexes (Nagy et al, 1997;Mantovani, 1999;Kakizawa et al, 2001;Park et al, 2002;Peng and Jahroudi, 2003;Huang et al, 2005). We therefore assessed the contribution of these factors to GADD45g promoter activity regulation.…”

Section: Resultsmentioning

confidence: 99%

“…NF-Y recruits the histone acetylase PCAF to promoters (Park et al, 2002;Huang et al, 2005). The participation of PCAF in the regulation of the GADD45g promoter was addressed by co-transfecting a PCAF expression plasmid with the À818 to þ 15 promoter reporter plasmid.…”

Section: Resultsmentioning

confidence: 99%

“…Since Oct-1 and NF-Y can interact with HATcontaining co-activator complexes and HDAC-containing co-repressor complexes (Nagy et al, 1997;Mantovani, 1999;Kakizawa et al, 2001;Park et al, 2002;Peng and Jahroudi, 2003;Huang et al, 2005), we studied the possible role of SMRT, HDAC1, and PCAF in the regulation of the murine GADD45g promoter. SMRT or HDAC1, but not HDAC3, ectopic expression reduced GADD45g promoter activity, while forced expression of PCAF increased it.…”

Section: Discussionmentioning

confidence: 99%

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The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

2007

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The GADD45c protein is a potential tumor suppressor whose expression is reduced in several tumors. However, very little is known about the regulation of its expression. We have determined that the most relevant region of its promoter lies between nucleotides À112 and À54, relative to the transcription start site. Putative Oct and NF-Y elements were found in this region and factors belonging to these families interacted with these elements in vitro and with the promoter in vivo. Mutation of these elements reduced the basal activity of the promoter, suggesting that both sites are essential for basal expression. These factors interact with chromatin modifying proteins and we found that histone deacetylase 1 or silencing mediator for retinoid and thyroid hormone receptor overexpression reduced the basal activity of the promoter. In contrast, forced expression of the histone acetylase protein PCAF or cell treatment with the HDAC inhibitor trichostatin A increased GADD45c mRNA levels and induced GADD45c promoter activity through its Oct and NF-Y elements. Moreover, ectopic expression of a dominantnegative version of NF-YA strongly inhibited trichostatin A-induced activation of the promoter. Our data strongly suggest that inhibition of deacetylase activity could potentially be used for treatment of tumors where GADD45c expression is reduced.

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Transcriptional Regulation of the Transforming Growth Factor β Type II Receptor Gene by Histone Acetyltransferase and Deacetylase Is Mediated by NF-Y in Human Breast Cancer Cells

Cited by 77 publications

References 31 publications

Restoration of Transforming Growth Factor-β Signaling through Receptor RI Induction by Histone Deacetylase Activity Inhibition in Breast Cancer Cells

Restoration of Transforming Growth Factor-β Signaling through Receptor RI Induction by Histone Deacetylase Activity Inhibition in Breast Cancer Cells

Posttranslational Regulation of NF-YA Modulates NF-Y Transcriptional Activity

The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

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