Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3‑kinase/protein kinase B signaling

Chen, Xiaofeng; Kuang, Weiping; Huang, Hongxing; Li, Bo; Zhu, Yong; Zhou, Bin; Yang, Lin

doi:10.3892/etm.2018.6135

Cited by 5 publications

(5 citation statements)

References 29 publications

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“…RSUME was found to be expressed in several types of tumors with high angiogenic potential 17 , 27 – 30 . RSUME is expressed in tissues prone to tumor development in VHL syndrome 17 and is upregulated in several tumors related to this disease 21 .…”

Section: Discussionmentioning

confidence: 99%

von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

et al. 2019

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Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.

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Section: Discussionmentioning

confidence: 99%

von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

et al. 2019

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Section: Rsume Overviewmentioning

confidence: 99%

“…In glioblastoma tumors, RSUME is overexpressed and correlates with shorter overall survival time of patients ( 10 ). Mechanistically, RSUME downregulation in glioblastoma cancer cells leads to diminished proliferative and invasive abilities by modulation of the PI3K/AKT signaling ( 10 ). It is important to note that the distribution of RSUME proteoforms differs between glioma samples, demonstrating that while the shorter RSUME proteoform is present in all gliomas studied, the longest RSUME proteoform is differentially expressed in those samples ( 3 ).…”

Section: Rsume Overviewmentioning

confidence: 99%

Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

et al. 2022

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The small RWD domain-containing protein called RSUME or RWDD3 was cloned from pituitary tumor cells with increasing tumorigenic and angiogenic proficiency. RSUME expression is induced under hypoxia or heat shock and is upregulated, at several pathophysiological stages, in tissues like pituitary, kidney, heart, pancreas, or adrenal gland. To date, several factors with essential roles in endocrine-related cancer appear to be modulated by RWDD3. RSUME regulates, through its post-translational (PTM) modification, pituitary tumor transforming gene (PTTG) protein stability in pituitary tumors. Interestingly, in these tumors, another PTM, the regulation of EGFR levels by USP8, plays a pathogenic role. Furthermore, RSUME suppresses ubiquitin conjugation to hypoxia-inducible factor (HIF) by blocking VHL E3-ubiquitin ligase activity, contributing to the development of von Hippel-Lindau disease. RSUME enhances protein SUMOylation of specific targets involved in inflammation such as IkB and the glucocorticoid receptor. For many of its actions, RSUME associates with regulatory proteins of ubiquitin and SUMO cascades, such as the E2-SUMO conjugase Ubc9 or the E3 ubiquitin ligase VHL. New evidence about RSUME involvement in inflammatory and hypoxic conditions, such as cardiac tissue response to ischemia and neuropathic pain, and its role in several developmental processes, is discussed as well. Given the modulation of PTMs by RSUME in neuroendocrine tumors, we focus on its interactors and its mode of action. Insights into functional implications and molecular mechanisms of RSUME action on biomolecular modifications of key factors of pituitary adenomas and renal cell carcinoma provide renewed information about new targets to treat these pathologies.

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“…The pituitary tumour cell from which RSUME was cloned showed increased tumorigenic and angiogenic potential when experimentally injected into nude mice with respect to a control GH3 stable cell line. Beside pituitary adenomas, RSUME was found to be expressed in other types of tumours with high angiogenic potential, among them gliomas (28) and pancreatic neuroendocrine tumours (29). Particularly, RSUME is expressed in tissues prone to tumour development in Von Hippel Lindau (VHL) syndrome and is upregulated in several tumours related to this disease (27,30).…”

Section: Expression and Function Of Rsume In Pituitary Tumoursmentioning

confidence: 99%

GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours

Stalla

Dimopoulou

Jung-Sievers

et al. 2020

European Journal of Endocrinology

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Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing’s disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing’s disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.

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Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3‑kinase/protein kinase B signaling

Cited by 5 publications

References 29 publications

von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME

Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours

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