Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation

Ma, Li; Huang, Chao; Wang, Xiongjun; Xin, Dazhuan; Wang, Li‐Shun; Zou, Quanli C.; Zhang, Yanan S.; Tan, Mengyao; Wang, Yumei; Zhao, Ting C.; Chatterjee, Devasis; Altura, Rachel A.; Wang, Chuangui; Xu, Yan; Yang, Jinghua; Fan, Yongsheng; Han, Baohui; Si, Jianmin; Zhang, Xiaoren; Cheng, Jinke; Chen, Zhijie; Chin, Y. Eugene

doi:10.1016/j.molcel.2016.12.002

Cited by 83 publications

(91 citation statements)

References 53 publications

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“…S7B]. Thus, other deacetylases, such as HDACs, other Sirtuins, or the Lysyl Oxidase 3, all previously described to deacetylate STAT3 (41)(42)(43), might also play a role. STAT3 acetylation is normally catalyzed by the acetyltransferases p300/CBP (19,41).…”

Section: Discussionmentioning

confidence: 97%

The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3

et al. 2019

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Epigenetic silencing of promoter and enhancer regions is a common phenomenon in malignant cells. The transcription factor STAT3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repression of a number of tumor suppressor genes (TSG) via molecular mechanisms that remain to be understood. Using nucleophosmin-anaplastic lymphoma kinase-positive (NPM-ALK þ) anaplastic large-cell lymphoma (ALCL) as model system, we found in cells and patient-derived tumor xenografts that STAT3 is constitutively acetylated as a result of ALK activity. STAT3 acetylation relied on intact ALK-induced PI3K-and mTORC1-dependent signaling and was sensitive to resveratrol. Resveratrol lowered STAT3 acetylation, rescued TSG expression, and induced ALCL apoptotic cell death. STAT3 constitutively bound the Sin3A transcriptional repressor complex, and both STAT3 and Sin3A bound the promoter region of silenced TSG via a resveratrol-sensitive mechanism. Silencing SIN3A caused reexpression of TSG, induced ALCL apoptotic cell death in vitro, and hindered ALCL tumorigenic potential in vivo. A constitutive STAT3-Sin3A interaction was also found in breast adenocarcinoma cells and proved critical for TSG silencing and cell survival. Collectively, these results suggest that oncogenedriven STAT3 acetylation and its constitutive association with Sin3A represent novel and concomitant events contributing to STAT3 oncogenic potential. Significance: This study delineates the transcriptional regulatory complex Sin3A as a mediator of STAT3 transcriptional repressor activity and identifies the STAT3/Sin3A axis as a druggable target to antagonize STAT3-addicted tumors.

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Section: Discussionmentioning

confidence: 97%

The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3

et al. 2019

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“…Signal Transducer and Activator of Transcription 3 (STAT3) is also a ubiquitous transcription factor that is a part of the JAK/STAT pathway. STAT3 influences the host immune response, cell cycle regulation, growth factors regulation, cell transformation, and many other cellular processes [160][161][162]. In order to bind DNA, Tyr-709 of STAT3 is phosphorylated followed by the formation of a homodimer via its SH2 domain before entering the nucleus and binding to the consensus sequence TTCCCGGAA [163].…”

Section: Signal Transducer and Activator Of Transcriptionmentioning

confidence: 99%

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

Turton

Meier-Stephenson

Badmalia

et al. 2020

Viruses

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The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.

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“…EOC cells secrete cytokines, including IL-1β, IL-6, and IL-23, which are involved in the expansion of CD4 + Th17 cell population (Figure 1), through activation of STAT3 [120,121]. Phosphorylation and acetylation profiles of STAT3 determine the differentiation and polarization of CD4 + Th17 cells that form the majority of tumor infiltrated T cells [122,123]. An increase in the Th17 cell population sustains the secretion of more cytokines (IL-17, IL-23) that eventually stimulates the release of angiogenesis factors VEGF and TGFβ in fibroblasts and endothelial cells.…”

Section: Immune Functionmentioning

confidence: 99%

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

Sundararajan

Sheu

et al. 2019

Cancers

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Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

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Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation

Cited by 83 publications

References 53 publications

The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3

The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

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