A new role for STAT3 as a regulator of chromatin topology

Zhao, Yunjie; Zeng, Chen; Tarasova, Nadya I.; Chasovskikh, Sergey; Dritschilo, Anatoly; Timofeeva, Olga

doi:10.4161/trns.27368

Cited by 26 publications

(24 citation statements)

References 34 publications

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“…In each condition, STAT3 binding sites were significantly closer to differentially expressed gene TSSs than random transcripts, which is consistent with regulation of gene expression. These findings suggest STAT3 acts more as a distal regulator in the context of TNBC, supporting previous findings of STAT3 distal gene regulation during normal development and in disease states [26]. …”

Section: Resultssupporting

confidence: 90%

Genomic regulation of invasion by STAT3 in triple negative breast cancer

et al. 2016

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Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 5 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.

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Section: Resultssupporting

confidence: 90%

Genomic regulation of invasion by STAT3 in triple negative breast cancer

et al. 2016

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“…In an analogous manner, uStat3 dimer formation was found to be dependent upon N‐terminal binding between monomers . Unique from the pStat3 tetramer binding motif, the orientation of DNA‐bound uStat3 dimers was found to simultaneously bind at two distant DNA binding domains of a single DNA by looping of the strand . Though DNA looping by this mechanism is believed to permit binding of a single GAS sequence, this finding suggests Stat3 regulation of chromatin remodeling as it both activates and represses gene expression during oncogenesis .…”

Section: Introductionmentioning

confidence: 92%

“…Successful binding of each tetramerized pStat3 dimer to DNA was found to be contingent upon bending of the DNA fragment containing GAS consensus sequences . In an analogous manner, uStat3 dimer formation was found to be dependent upon N‐terminal binding between monomers . Unique from the pStat3 tetramer binding motif, the orientation of DNA‐bound uStat3 dimers was found to simultaneously bind at two distant DNA binding domains of a single DNA by looping of the strand .…”

Section: Introductionmentioning

confidence: 92%

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Non‐canonical Stat3 signaling in cancer

Srivastava

DiGiovanni

2015

Molecular Carcinogenesis

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Stat3 is a member of the signal transducers and activators of transcription family and is a known regulator of essential biologic processes including angiogenesis, apoptosis, cell cycle progression, and cell migration. Canonical Stat3-mediated signaling involves tyrosine phosphorylation on specific residues that leads to homodimerization and translocation to the nucleus. For many years it was presumed that most, if not all, of the functions of Stat3, both normal and aberrant, were due to the canonical cytokine and growth factor signaling mechanisms. Recent studies suggest that Stat3 functions through alternate non-canonical pathways to bring about some of these biological functions both in normal cells as well as during cancer development and progression. A number of studies have now shown that Stat3 has a function in mitochondria and that unphosphorylated Stat3 (uStat3) can also function as a transcription factor broadening the potential mechanisms involved in Stat3 action. In this review article, we discuss these two main non-canonical functions of Stat3 and their potential roles in oncogenesis. Given the many facets of Stat3 signaling, additional comprehensive investigations are required to fully understand the role of non-canonical Stat3 signaling in cancer and whether these pathways can be targeted for cancer prevention and treatment. © 2015 Wiley Periodicals, Inc.

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“…However, the full complement of target genes dependent on the STAT3 NTD has not been determined. Second, the NTD mediates dimerization of unphosphorylated STAT3 (U-STAT3) and is essential for its nuclear accumulation (14)(15)(16), DNA binding (17), chromatin remodeling (17)(18)(19), and regulation of gene expression (18). A point mutation in the NTD (L78R) that disrupts U-STAT3 dimerization has been identified in inflammatory hepatocellular adenoma (IHCA) (20,21).…”

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confidence: 99%

Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity

Hu¹,

Yeh

Pinello

et al. 2015

Molecular and Cellular Biology

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The transcription factor STAT3 is constitutively active in many cancers, where it mediates important biological effects, including cell proliferation, differentiation, survival, and angiogenesis. The N-terminal domain (NTD) of STAT3 performs multiple functions, such as cooperative DNA binding, nuclear translocation, and protein-protein interactions. However, it is unclear which subsets of STAT3 target genes depend on the NTD for transcriptional regulation. To identify such genes, we compared gene expression in STAT3-null mouse embryonic fibroblasts (MEFs) stably expressing wild-type STAT3 or STAT3 from which NTD was deleted. NTD deletion reduced the cytokine-induced expression of specific STAT3 target genes by decreasing STAT3 binding to their regulatory regions. To better understand the potential mechanisms of this effect, we determined the crystal structure of the STAT3 NTD and identified a dimer interface responsible for cooperative DNA binding in vitro. We also observed an Ni 2؉ -mediated oligomer with an as yet unknown biological function. Mutations on both dimer and Ni 2؉ -mediated interfaces affected the cytokine induction of STAT3 target genes. These studies shed light on the role of the NTD in transcriptional regulation by STAT3 and provide a structural template with which to design STAT3 NTD inhibitors with potential therapeutic value.

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A new role for STAT3 as a regulator of chromatin topology

Cited by 26 publications

References 34 publications

Genomic regulation of invasion by STAT3 in triple negative breast cancer

Genomic regulation of invasion by STAT3 in triple negative breast cancer

Non‐canonical Stat3 signaling in cancer

Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity

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