PIASy mediates hypoxia-induced <i>SIRT1</i> transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells

Sun, Lina; He, Li; Chen, Junliang; Iwasaki, Yoshinobu; Kubota, Takeshi; Matsuoka, Masao; Shen, Aiguo; Chen, Qi; Xu, Yong

doi:10.1242/jcs.127381

Cited by 75 publications

(60 citation statements)

References 58 publications

(53 reference statements)

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“…Cells experiencing EMT can also reactivate stem cell-associated self-renewal programs, which suppose some degrees of plasticity (66). Several reports suggest that hypoxia promotes EMT in various cancer types, including prostate, breast, renal, pancreatic, myeloma, lung, ovarian, and squamous carcinoma (6,46,62,64,97,100,108). Experimental studies have revealed that the stabilization of HIF-1␣ by hypoxia can directly or indirectly stimulate the expression of several E-box-binding transcription factors known to regulate EMT, including TWIST1, ZEB2, and SNAIL (64,90,121,124), while discrepancies among models suggest context-dependent events.…”

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

320

310

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-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

320

310

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“…prostate Overexpression of PIAS1 [122,123] Overexpression of PIAS3 [124] breast Overexpression of PIAS1 [125] Overexpression of PIAS3 [124] multiple myeloma Overexpression of PIAS1 [120] gastric Downregulation of PIAS3 [126] lung Overexpression of PIAS3 [124] brain Overexpression of PIAS3 [124] ovaries Expression of PIASγ correlates with cancer aggressiveness [127] pancreas Overexpression of PIASγ [128] RanBP2 small cell lung cancer Upregulation of RanBP2 compared to non-small cell lung cancer [129] leukemia Expressed as RanBP2-ALK fusion protein [130] SUMO proteases SENP1, SENP1, SENP2, SENP3, SENP5, SENP6, SENP7…”

Section: Figure 2 Sumoylation Of Important Cell Cycle Regulatorsmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

234

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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“…Reverse transcription reactions were performed as previously described using a SuperScript First-Strand Synthesis System (Invitrogen). 47 Primers and Taqman probes used for real-time reactions were purchased from Applied Biosystems.…”

Section: Rna Isolation and Real-time Pcrmentioning

confidence: 99%

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Xu¹,

Qin³

et al. 2015

Journal of the American Society of Nephrology

Self Cite

111

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Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellular matrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia. However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice with DN, MRTF-A was induced by glucose and synergized with glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed that MRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis.

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PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells

Cited by 75 publications

References 58 publications

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

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