STAT3‐Interacting Proteins as Modulators of Transcription Factor Function: Implications to Targeted Cancer Therapy

Yeh, Jennifer; Frank, David A.

doi:10.1002/cmdc.201500482

Cited by 35 publications

(22 citation statements)

References 84 publications

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“…SOCS3 also negatively regulates JAK-STAT3, p44/P42 MAPK, and p53 in prostate and hepatocellular cancer [27][28][29] . STAT3interacting proteins, including chromatin remodeling proteins such as BRG1 and oncogenic transcription factors such as nuclear factor kB (NF-kB) or nuclear factor of activated T cells 1 (NFATc1), have been reported to function as either positive or negative regulators in many types of cancers 30 . Of the positive regulators, annexin A2 binds to STAT3 C-terminal domain containing transactivation domain (TAD) and enhances STAT3 activity, thereby promoting epithelial-to-mesenchymal transition in breast cancer 31 .…”

Section: Introductionmentioning

confidence: 99%

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells

Kim

Lee

et al. 2020

Oncogenesis

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DNA damage-induced apoptosis suppressor (DDIAS) regulates cancer cell survival. Here we investigated the involvement of DDIAS in IL-6-mediated signaling to understand the mechanism underlying the role of DDIAS in lung cancer malignancy. We showed that DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in malignant cancers. Interestingly, siRNA protein tyrosine phosphatase (PTP) library screening revealed protein tyrosine phosphatase receptor mu (PTPRM) as a novel STAT3 PTP. PTPRM knockdown rescued the DDIAS-knockdown-mediated decrease in STAT3 Y705 phosphorylation in the presence of IL-6. However, PTPRM overexpression decreased STAT3 Y705 phosphorylation. Moreover, endogenous PTPRM interacted with endogenous STAT3 for dephosphorylation at Y705 following IL-6 treatment. As expected, PTPRM bound to wild-type STAT3 but not the STAT3 Y705F mutant. PTPRM dephosphorylated STAT3 in the absence of DDIAS, suggesting that DDIAS hampers PTPRM/STAT3 interaction. In fact, DDIAS bound to the STAT3 transactivation domain (TAD), which competes with PTPRM to recruit STAT3 for dephosphorylation. Thus we show that DDIAS prevents PTPRM/STAT3 binding and blocks STAT3 Y705 dephosphorylation, thereby sustaining STAT3 activation in lung cancer. DDIAS expression strongly correlates with STAT3 phosphorylation in human lung cancer cell lines and tissues. Thus DDIAS may be considered as a potential biomarker and therapeutic target in malignant lung cancer cells with aberrant STAT3 activation.

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Section: Introductionmentioning

confidence: 99%

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells

Kim

Lee

et al. 2020

Oncogenesis

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“…Therefore, STAT3 PTMs are specific and reflect particular cell conditions and they may be implicated in PCa development and progression. Our efforts are focused on understanding the correlation between STAT3 PTMs, as well as STAT3 protein interactors and gene expression at different clinical tumor stages [27]. The protein interactors analyzed are: CBP/p300 (Histone Acetyltransferase p300 interactor), directly responsible for STAT3 acetylation [28], PDIA3/ERp57 [29] and APE1/Ref-1 [30] modulators of oxidative stress conditions.…”

Section: Introductionmentioning

confidence: 99%

Analysis of STAT3 post-translational modifications (PTMs) in human prostate cancer with different Gleason Score

et al. 2017

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Prostate Cancer (PCa) is a complex and heterogeneous disease. The androgen receptor (AR) and the signal transducer and activator of transcription 3 (STAT3) could be effective targets for PCa therapy. STAT3, a cytoplasmatic latent transcription factor, is a hub protein for several oncogenic signalling pathways and up-regulates the expression of numerous genes involved in tumor cell proliferation, angiogenesis, metastasis and cell survival. STAT3 activity can be modulated by several Post-Translational Modifications (PTMs) which reflect particular cell conditions and may be implicated in PCa development and progression. The aim of this work was to analyze STAT3 PTMs at different tumor stages and their relationship with STAT3 cellular functions. For this purpose, sixty-five prostatectomy, Formalin-fixed paraffin-embedded (FFPE) specimens, classified with different Gleason Scores, were subjected to immunoblotting, immunofluorescence staining and RT-PCR analysis. All experiments were carried out in matched non-neoplastic and neoplastic tissues. Data obtained showed different STAT3 PTMs profiles among the analyzed tumor grades which correlate with differences in the amount and distribution of specific STAT3 interactors as well as the expression of STAT3 target genes. These results highlight the importance of PTMs as an additional biomarker for the exactly evaluation of the PCa stage and the optimal treatment of this disease.

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“…STAT3 is well demonstrated to play a crucial role in tumorigenesis and cancer-related inflammation [35]. Persistent activation of STAT3 signaling is involved in promoting tumor cell proliferation, metastasis, invasion, angiogenesis and immunosuppression [36, 37]. There are several earlier studies, albeit conflicting, reporting crosstalks between TGF-β and STAT3 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling

Tang

Shen

et al. 2016

Oncotarget

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IL-37 has been characterized as a fundamental inhibitor of innate immunity and a tumor suppressor in several cancers. However, the molecular mechanism of IL-37 in hepatocellular carcinoma (HCC) is largely unclear. In this study we found IL-37 expression was down-regulated in human HCC tissues and cell lines, and was negatively correlated with tumor size, vascular invasion, as well as overall-survial and disease-free survival (OS and DFS) of HCC. Multivariate Cox analysis revealed that IL-37 was an independent prognostic indicator for OS and DFS in HCC. Functional studies further showed that IL-37 overexpression significantly suppressed tumor growth by confining HCC to G2/M cell cycle arrest in vitro and in vivo. Mechanistically, we determined that IL-37 promoted Smad3 phospho-isoform signaling conversion from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/p21 tumor-suppressive signaling. Consistently, we detected a significant negative correlation between IL-37 expression and pSmad3L levels in a cohort of HCC biopsies; and the expression of pSmad3L predicted poorer outcome. These data highlight the importance of IL-37 in the cell proliferation and progression of HCC, and suggests that IL-37 may be a valuable biomarker for HCC prognosis.

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STAT3‐Interacting Proteins as Modulators of Transcription Factor Function: Implications to Targeted Cancer Therapy

Cited by 35 publications

References 84 publications

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells

Analysis of STAT3 post-translational modifications (PTMs) in human prostate cancer with different Gleason Score

IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling

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