STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination

Jung, Jae-Chul; Kim, Hong Sook; Lee, Chang Seok; Shin, Yong Jae; Kim, Yong Nyun; Kang, Gyeong Hoon; Kim, Tae You; Juhnn, Yong Sung; Kim, Sung Joon; Park, Jong-Wan; Ye, Sang Kyu; Chung, Myung Hee

doi:10.3858/emm.2008.40.5.479

Cited by 104 publications

(97 citation statements)

References 23 publications

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“…Although STAT3 is known as a transcriptional factor, STAT3-mediated regulation of MGMT did not depend on its transcriptional activity. Recently, it has been reported that active STAT3 is involved in protein stabilization through inhibition of the ubiquitylation of the target molecule (41), and consistent with this report, we observed that MGMT downregulation by STAT3 inhibitor was recovered partially by the proteasome inhibitor MG132 treatment. However, it should be noted that ubiquitylated levels of MGMT were unchanged after STAT3 inhibitor treatment (data not shown).…”

Section: Discussionsupporting

confidence: 81%

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Wang

Yachi

Mahabir

et al. 2012

Molecular Cancer Therapeutics

167

139

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Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r ¼ 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.

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Section: Discussionsupporting

confidence: 81%

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

Wang

Yachi

Mahabir

et al. 2012

Molecular Cancer Therapeutics

167

139

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“…STAT3 has been shown to positively regulate HIF1a expression through transcriptional and posttranscriptional mechanisms (37,38,59). However, we showed that STAT3-deficient TCCs expressed slightly higher levels of HIF1α and its transcriptional targets compared with controls, suggesting a paradoxical role for STAT3 as a negative regulator of HIF1α.…”

Section: Discussionmentioning

confidence: 55%

“…CoCl 2 stabilizes the HIF1α in normoxia, impeding its proteasomaldependent degradation (36). STAT3 has been shown to both transcriptionally regulate HIF1α and impede its degradation through the sequestration of the von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase (VHL-E3) (37,38). We observed that CoCl 2 induced HIF1α accumulation at similar levels in both shCT and shSTAT3 cells (Fig.…”

Section: Igfbp7mentioning

confidence: 59%

STAT3 negatively regulates thyroid tumorigenesis

Couto

Daly²,

Almeida

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

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Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.cytokine | tumor microenvironment | metabolic reprogramming P apillary thyroid carcinoma (PTC) is the most common endocrine malignancy in humans (1); 70% of PTCs harbor alterations in receptor tyrosine kinases or their downstream effectors that activate the ERK/MAPK pathway (2), namely v-RAF murine sarcoma viral oncogene homolog B (BRAF) V600E mutations, rearranged during transfection (RET)/PTC rearrangements, and rat sarcoma virus oncogene (RAS) mutations (3). Although these oncogenic alterations have been extensively studied, other factors, particularly those factors mediating the interaction between the tumor and the surrounding microenvironment, have not been fully characterized (4). PTCs often display an immune cell and desmoplastic stromal infiltrate associated with increased IL-6 and IFNγ, although the precise role of the inflammatory mediators is not yet known (5).IL-6 plays an important part in immune cell development and behavior (6). This cytokine signals through a dual receptor system comprising a membrane or soluble receptor for IL-6 (IL-6R) and the signal transducing component, gp130, which is common to the IL-6 family of cytokines (7). Engagement of IL-6 with the IL-6R and gp130 leads to...

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“…On the one hand, STAT3 transcriptionally upregulates HIF1A; 47 on the other hand, STAT3 interacts with the C-terminal domain of HIF1A and stabilizes the protein from ubiquitination mediated by VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase). 48 Interestingly, HIF1A may also modulate autophagy in a context-dependent manner. HIF is a heterodimer of a constitutive b subunit and an oxygen-regulated a subunit 50 demonstrates that the stable overexpression of HIF1A reverses the induction of autophagy by the JAK2-STAT3 inhibitor cucurbitacin I in U251 cells.…”

Section: Stat3 In Autophagymentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

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Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

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STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination

Cited by 104 publications

References 23 publications

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression

STAT3 negatively regulates thyroid tumorigenesis

The role of STAT3 in autophagy

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