Renal medullary carcinomas depend upon<i>SMARCB1</i>loss and are sensitive to proteasome inhibition

Hong, Andrew L.; Tseng, Yuen-Yi; Wala, Jeremiah A.; Kim, Won Jun; Kynnap, Bryan D.; Doshi, Mihir B.; Kugener, Guillaume; Sandoval, Gabriel J.; Howard, Thomas P.; Li, Ji; Yang, Xiaoping; Tillgren, Michelle; Ghandi, Mahmoud; Sayeed, Abeer; Deasy, Rebecca; Ward, Abigail; McSteen, Brian; Labella, Katherine; Keskula, Paula; Tracy, Adam; Connor, Cora; Clinton, Catherine; Church, Alanna J.; Crompton, Brian D.; Janeway, Katherine A.; Hare, Barbara Van; Sandak, David; Gjoerup, Ole; Bandopadhayay, Pratiti; Clemons, Paul A.; Schreiber, Stuart L.; Root, David E.; Gokhale, Prafulla C.; Susan, N.; Mullen, Elizabeth; Roberts, Charles W.M.; Kadoch, Cigall; Beroukhim, Rameen; Ligon, Keith L.; Boehm, Jesse S.; Hahn, William C.

doi:10.1101/487579

Cited by 12 publications

(22 citation statements)

References 77 publications

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“…A single research reported the possibility that SMARCB1 might be involved in regulating UPS activity through modulating the transcription of UPS-related proteins [ 35 ]. Moreover, using computational modeling, the conserved imperfect repeat unit (Rpt1) domain of SMARCB1 was identified to share structural similarity with the PLAA family of the ubiquitin-binding (PFU) domain of phospholipase A2-activating protein (PLAA) which is required for the interaction with ubiquitin [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury

Zhu

Sheng

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nuclear receptor subfamily 4 group A member 3 (NR4A3) protects the vascular endothelial cell (VEC) against hypoxia stress, whose expression is primarily reported to be governed at a transcriptional level. However, the regulation of NR4A3 in the protein level is largely unknown. Here, we report that NR4A3 protein abundance is decreased immensely in VEC injury induced by reoxygenation after oxygen-glucose deprivation (OGD-R), which is significantly blocked by the administration of the antioxidative steroid TRIOL. Moreover, the notable improvement of NR4A3 and the alleviation of pulmonary endothelial barrier hyperpermeability induced by acute hypobaric hypoxia in cynomolgus monkeys are also observed after TRIOL administration. The overproduction of reactive oxygen species (ROS) decreases NR4A3 protein abundance in VEC under OGD-R condition, which is reversed by TRIOL and N-acetylcysteine (NAC). TRIOL dose-dependently increases the NR4A3 protein level by inhibiting ubiquitination and ubiquitin proteasome system- (UPS-) mediated degradation rather than promoting its transcription. Using yeast two-hybrid screening, we further identify the interaction between NR4A3 and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and the DNA-binding domain of NR4A3 is required for this interaction. Knockdown of SMARCB1 reduces ubiquitination and degradation of NR4A3, suggesting the proubiquitylation effect of this interaction which is enhanced by ROS in VEC injury induced by OGD-R. In summary, our study here for the first time reveals a posttranslational regulation in SMARCB1-mediated NR4A3 protein degradation which is driven by ROS, providing further understanding of the impaired regulation of NR4A3-mediated prosurvival pathways under pathological condition in VEC.

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Section: Resultsmentioning

confidence: 99%

SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury

Zhu

Sheng

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Microscopically, RMC tumors are densely packed with eosinophilic‐cytoplasmic epithelial cells in cribriform orientation and cytoplasmic inclusions (Swartz et al, ). Interestingly, patients with RMC also harbor deletions in SMARCB1 , similar to RTK (Cheng et al, ; Fox et al, ; Hong et al, ; Msaouel, Tannir, & Walker, ; Table ). However, unlike RTK, which has very few other recurrent genetic events, RMC is also associated with t(2;10)(p23.2;q22.2) translocation that leads to anaplastic lymphoma kinase (ALK) and vinculin fusions (Mariño‐Enríquez et al, ).…”

Section: Renal Cell Tumors: Most Common Renal Malignancies In Adultsmentioning

confidence: 99%

Lessons learned from the developmental origins of childhood renal cancer

Chong

Cain

2019

The Anatomical Record

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Despite the rarity of renal tumors in children, many different types of malignant and nonmalignant renal neoplasms have been described. Therefore, the correct diagnosis and clinical management of these patients can represent a challenge. Here we provide a comprehensive review of the commonly diagnosed pediatric renal malignancies, including nephroblastoma (commonly known as Wilms tumor), clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, several subtypes of renal cell tumors (often collectively termed renal cell carcinoma), and congenital mesoblastic nephroma. The epidemiology, pathology, treatments, underlying genetic and molecular mechanisms, and proposed developmental origins are discussed in detail, highlighting differential features and potential improved therapeutic strategies for affected individuals.

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“…Currently, there is a need for cell line models for RMC to provide a crucial tool for the investigation of novel therapies for patients affected with RMC. A recent study by Hong et al 20 managed to produce two primary tumor cell lines from two separate patients using a ROCK inhibitor (Y‐27632) based methodology 21 to produce a successful culture. Both cell lines and the tumors from which they were derived had the expected loss of SMARCB1 function and the cell lines demonstrated an in vitro response to bortezomib 20 .…”

Section: Introductionmentioning

confidence: 99%

“…A recent study by Hong et al 20 managed to produce two primary tumor cell lines from two separate patients using a ROCK inhibitor (Y‐27632) based methodology 21 to produce a successful culture. Both cell lines and the tumors from which they were derived had the expected loss of SMARCB1 function and the cell lines demonstrated an in vitro response to bortezomib 20 . Neither of the primary tumor lines developed in this study were capable of producing tumor xenografts and so this study relied on utilizing the SMARCB1‐deficient rhabdoid cell line G401 as a substitute for an actual RMC cell line in its in vivo studies 20 .…”

Section: Introductionmentioning

confidence: 99%

“…Both cell lines and the tumors from which they were derived had the expected loss of SMARCB1 function and the cell lines demonstrated an in vitro response to bortezomib 20 . Neither of the primary tumor lines developed in this study were capable of producing tumor xenografts and so this study relied on utilizing the SMARCB1‐deficient rhabdoid cell line G401 as a substitute for an actual RMC cell line in its in vivo studies 20 . Confirmation of in vitro data by in vivo analysis is fundamentally important for the evaluation of therapeutic agents; thus, a model that allows for in vivo analysis is essential.…”

Section: Introductionmentioning

confidence: 99%

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Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutic treatments

Wei

Yang

Ricketts

et al. 2020

Genes Chromosomes & Cancer

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Renal medullary carcinoma (RMC) is a rare, aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses with a median overall survival of 13 months. Patients are typically young (median age-22) and male (male:female ratio of 2:1) and tumors are characterized by complete loss of expression of the SMARCB1 tumor suppressor protein. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to better understand the pathogenesis of this disease and to identify effective forms of therapy. Two novel cell line models, UOK353 and UOK360, were derived from primary RMCs that both demonstrated the characteristic SMARCB1 loss. Both cell lines overexpressed EZH2 and other members of the polycomb repressive complex and EZH2 inhibition in RMC tumor spheroids resulted in decreased viability. High throughput drug screening of both cell lines revealed several additional candidate compounds, including bortezomib that had both in vitro and in vivo antitumor activity. The activity of bortezomib was shown to be partially dependent on increased oxidative stress as addition of the Nacetyl cysteine antioxidant reduced the effect on cell proliferation. Combining bortezomib and cisplatin further decreased cell viability both in vitro and in vivo that single agent bortezomib treatment. The UOK353 and UOK360 cell lines represent novel preclinical models for the development of effective forms of therapy for RMC patients. K E Y W O R D S Bortezomib, EZH2 inhibitor, INI1, renal medullary carcinoma, RMC, SMARCB1, SWI/SNF complex, UOK353, UOK360

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Renal medullary carcinomas depend uponSMARCB1loss and are sensitive to proteasome inhibition

Abstract: 23 24 48 identify a synthetic lethal relationship that may serve as a therapeutic approach for patients with 49 SMARCB1 deficient cancers. 50 51 52

Cited by 12 publications

References 77 publications

SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury

SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury

Lessons learned from the developmental origins of childhood renal cancer

Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutic treatments

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