Differential Regulation of Estrogen Receptor α Expression in Breast Cancer Cells by Metastasis-Associated Protein 1

Kang, Hyunjin; Lee, Minho; Kang, Hae-Lim; Kim, Sung Hoon; Ahn, Jung-Ranh; Na, Hyelin; Na, Tae-Young; Kim, Yo Na; Seong, Je Kyung

doi:10.1158/0008-5472.can-13-2020

Cited by 65 publications

(79 citation statements)

References 43 publications

(54 reference statements)

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“…Though IFI16 is known to be involved in transcriptional regulation [32]–[34], [48], [70]–[76], the mechanisms of this regulation have been largely undetermined. IFI16 may modulate transcription through association with transcription factors and/or blocking their association with promoters [33], [34], [45], [48], [70], [72]–[74] or it may promote the formation of heterochromatin on promoters, resulting in their repression [38], [76].…”

Section: Discussionmentioning

confidence: 99%

IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications

et al. 2014

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Interferon-γ inducible factor 16 (IFI16) is a multifunctional nuclear protein involved in transcriptional regulation, induction of interferon-β (IFN-β), and activation of the inflammasome response. It interacts with the sugar-phosphate backbone of dsDNA and modulates viral and cellular transcription through largely undetermined mechanisms. IFI16 is a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus (HSV-1), though the mechanisms of HSV-1 restriction are not yet understood. Here, we show that IFI16 has a profound effect on HSV-1 replication in human foreskin fibroblasts, osteosarcoma cells, and breast epithelial cancer cells. IFI16 knockdown increased HSV-1 yield 6-fold and IFI16 overexpression reduced viral yield by over 5-fold. Importantly, HSV-1 gene expression, including the immediate early proteins, ICP0 and ICP4, the early proteins, ICP8 and TK, and the late proteins gB and Us11, was reduced in the presence of IFI16. Depletion of the inflammasome adaptor protein, ASC, or the IFN-inducing transcription factor, IRF-3, did not affect viral yield. ChIP studies demonstrated the presence of IFI16 bound to HSV-1 promoters in osteosarcoma (U2OS) cells and fibroblasts. Using CRISPR gene editing technology, we generated U2OS cells with permanent deletion of IFI16 protein expression. ChIP analysis of these cells and wild-type (wt) U2OS demonstrated increased association of RNA polymerase II, TATA binding protein (TBP) and Oct1 transcription factors with viral promoters in the absence of IFI16 at different times post infection. Although IFI16 did not alter the total histone occupancy at viral or cellular promoters, its absence promoted markers of active chromatin and decreased those of repressive chromatin with viral and cellular gene promoters. Collectively, these studies for the first time demonstrate that IFI16 prevents association of important transcriptional activators with wt HSV-1 promoters and suggest potential mechanisms of IFI16 restriction of wt HSV-1 replication and a direct or indirect role for IFI16 in histone modification.

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Section: Discussionmentioning

confidence: 99%

IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications

et al. 2014

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“…qRT-PCR analysis for early viral transcripts showed that their expression was significantly lower in AdVIFI16-infected cells than in AdVLacZ-infected cells, especially at 48 h. The observed effect of IFI16 on the integrated HPV genome is consistent with its activity on viral and cellular promoters alongside its interaction with histone modification machinery. Indeed, IFI16 has been demonstrated to induce changes in markers for heterochromatin and euchromatin on viral and cellular promoters (21,33,51).…”

Section: Resultsmentioning

confidence: 99%

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

Cigno

Andrea

Borgogna

et al. 2015

J Virol

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The human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by inhibiting both viral-DNA replication and transcription. Through the use of two distinct cellular models, this study provides strong evidence in support of the notion that IFI16 can also restrict human papillomavirus 18 (HPV18) replication. In the first model, an immortalized keratinocyte cell line (NIKS) was used, in which the IFI16 protein was knocked down through the use of small interfering RNA (siRNA) technology and overexpressed following transduction with the adenovirus IFI16 (AdVIFI16) vector. The second model consisted of U2OS cells transfected by electroporation with HPV18 minicircles. In differentiated IFI16-silenced NIKS-HPV18 cells, viral-load values were significantly increased compared with differentiated control cells. Consistent with this, IFI16 overexpression severely impaired HPV18 replication in both NIKS and U2OS cells, thus confirming its antiviral restriction activity. In addition to the inhibition of viral replication, IFI16 was also able to reduce viral transcription, as demonstrated by viralgene expression analysis in U2OS cells carrying episomal HPV18 minicircles and HeLa cells. We also provide evidence that IFI16 promotes the addition of heterochromatin marks and the reduction of euchromatin marks on viral chromatin at both early and late promoters, thus reducing both viral replication and transcription. Altogether, these results argue that IFI16 restricts chromatinized HPV DNA through epigenetic modifications and plays a broad surveillance role against viral DNA in the nucleus that is not restricted to herpesviruses. IMPORTANCEIntrinsic immunity is mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The host nuclear factor IFI16 acts as a sensor of foreign DNA and an antiviral restriction factor, as recently demonstrated by our group for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1). Here, we provide the first evidence that IFI16 inhibits HPV18 replication by repressing viral-gene expression and replication. This antiviral restriction activity was observed in immortalized keratinocytes transfected with the religated genomes and in U2OS cells transfected with HPV18 minicircles, suggesting that it is not cell type specific. We also show that IFI16 promotes the assembly of heterochromatin on HPV DNA. These changes in viral chromatin structure lead to the generation of a repressive state at both early and late HPV18 promoters, thus implicating the protein in the epigenetic regulation of HPV gene expression and replication. Many recent studies point to the importance of cell-type-and host-specific expression of antiviral factors in limiting viral infection (1-4). Some of the very early antiviral responses include the activation of intrinsic restriction factors at h...

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“…Therefore, the results of the present study demonstrated that TAC chemotherapy combined with endocrine MPA therapy may effectively improve the prognosis and survival rates of patients with endometrial cancer. MTA1 is associated with the metastatic state in various types of cancer (9)(10)(11)(12)(13)(14)(15). For example, recent studies have demonstrated that MTA1 promotes tumor invasion in human esophageal (11) and laryngeal (14) squamous cell carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…MTA1 is associated with the metastatic state in various types of cancer (9)(10)(11)(12)(13)(14)(15). For example, recent studies have demonstrated that MTA1 promotes tumor invasion in human esophageal (11) and laryngeal (14) squamous cell carcinoma cells. In the present study, it was identified that combined use of MPA and TAC chemotherapy may significantly decrease the expression levels of MTA1 in patients with endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

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Endocrine MPA enhances the effects of TAC chemotherapy on improvement of prognosis and increase in long-term survival rates for patients with endometrial cancer

Yuan¹,

Wang²,

Xue³

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the effect of taxol, adriamycin and carboplatin (TAC) chemotherapy combined with endocrine medroxyprogesterone acetate (MPA) therapy for the treatment of patients with endometrial cancer. A retrospective analysis of 124 patients with endometrial cancer was performed by dividing the cohort into an experimental and control group. The 64 patients in the experimental group received TAC and MPA chemotherapy, whereas the 60 patients in the control group were treated with TAC chemotherapy only. Tissue samples scraped from the uterus were used to extract the total proteins and RNAs for the western blot and reverse transcription-quantitative polymerase chain reaction analyses, respectively. All the patients were followed up for 20-45 months, during which time prognostic data, and one-to three-year survival rates were recorded and compared. The rate of recurrence or metastasis was significantly lower in the experimental group compared with that in the control group (P<0.05) and the three-year survival rate of the experimental group was significantly higher than that of the control group (P<0.05). Furthermore, the mean metastasis-associated 1 (MTA1) protein and RNA expression levels were significantly lower in the experimental group compared with the control group (P<0.05), exhibiting ~30 and ~15% of the levels in the control group, respectively. Therefore, a treatment strategy of TAC chemotherapy combined with endocrine MPA therapy appears to effectively improve the prognosis and increase the long-term survival rates of patients with endometrial cancer. Such an enhancing effect may be mediated by the transcriptional downregulation of MTA1 expression. IntroductionEndometrial cancer is a common type of malignant gynecological disease that predominantly occurs in post-menopausal females, aged 50-60 years. It accounts for 20-30% of cases of female cancer, with the incidence rate demonstrating an increasing trend in recent years (1). Tumors in endometrial cancer patients at clinical stages I/II exhibit a low degree of differentiation and invasive ability, therefore, good results can be obtained using surgical intervention. By contrast, tumors in patients at stages III/IV exhibit a higher degree of malignancy and differentiation, therefore, surgical treatments are only able to reduce tumor volume. Instead, adjuvant endocrine therapy, radiotherapy, and chemotherapy are typically administered for patients at stages III and IV to effectively improve the survival rate (2-4).The taxol, adriamycin and carboplatin (TAC) chemotherapy regimen has gradually been utilized for the treatment of patients with advanced endometrial cancer. Compared with the traditional adriamycin/cisplatin and cyclophosphamide/adriamycin/cisplatin regimens, the effect of the TAC regimen is more pronounced, causing fewer side effects in patients. In particular, TAC exhibits lower hematological toxicity, thus, resulting in more comprehensive treatment and improved recovery for patients (5).Endocrine thera...

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Differential Regulation of Estrogen Receptor α Expression in Breast Cancer Cells by Metastasis-Associated Protein 1

Cited by 65 publications

References 43 publications

IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications

IFI16 Restricts HSV-1 Replication by Accumulating on the HSV-1 Genome, Repressing HSV-1 Gene Expression, and Directly or Indirectly Modulating Histone Modifications

The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters

Endocrine MPA enhances the effects of TAC chemotherapy on improvement of prognosis and increase in long-term survival rates for patients with endometrial cancer

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