Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

Teramachi, Jumpei; Silbermann, Rebecca; Yang, Peng; Zhao, Wei; Mohammad, Khalid S.; Guo, Jiaojiao; Anderson, Judith H.; Zhou, Dajun; Feng, Rentian; Myint, Kyaw Ze Yar; Maertz, Nathan; Beumer, Jan H.; Eiseman, Julie L.; Windle, Jolene J.; Xie, Xiang‐Qun; Roodman, G. David; Kurihara, N.

doi:10.1038/leu.2015.229

Cited by 46 publications

(54 citation statements)

References 31 publications

(48 reference statements)

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“…These cells showed a reduced proliferative capacity and an increase in apoptosis when they lost regulation of RIP1. They are supported by prior studies from Teramachi's laboratory who also observed that cell growth was inhibited by using the inhibitor XRK3F2 that specifically blocks the ZZ domain of p62 in myeloma cells . These results confirm our hypothesis that p62 can regulate the NF‐κB signaling pathway through the ubiquitination of RIP1 in ovarian cancer cells.…”

Section: Discussionsupporting

confidence: 89%

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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Platinum‐based therapeutic strategies have been widely used in ovarian cancer treatment. However, drug resistance has greatly limited therapeutic efficacy. Recently, tolerance to cisplatin has been attributed to other factors unrelated to DNA. p62 (also known as SQSTM1) functions as a multifunctional hub participating in tumorigenesis and may be a therapeutic target. Our previous study showed that p62 was overexpressed in drug‐resistant ovarian epithelial carcinoma and its inhibition increased the sensitivity to cisplatin. In this study, we demonstrate that the activity of the NF‐κB signaling pathway and K63‐linked ubiquitination of RIP1 was higher in cisplatin‐resistant ovarian (SKOV3/DDP) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using siRNA. Furthermore, deletion of the ZZ domain of p62 that interacts with RIP1 in SKOV3 cells markedly decreased K63‐linked ubiquitination of RIP1 and inhibited the activation of the NF‐κB signaling pathway. Moreover, loss of the ZZ domain from p62 led to poor proliferative capacity and high levels of apoptosis in SKOV3 cells and made them more sensitive to cisplatin treatment. Collectively, we provide evidence that p62 is implicated in the activation of NF‐κB signaling that is partly dependent on RIP1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.

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Section: Discussionsupporting

confidence: 89%

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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“…In a subsequent study, a novel small molecule inhibitor of signaling via the ZZ domain of p62 (Sequestosome 1), XRK3F2, blocked tumor necrosis factor (TNF) and multiple myeloma‐induced Gfi1 upregulation, resulting in decreased binding and recruitment of HDAC1 to the RUNX2 promoter in pre‐OBs . These results complement previous in vivo observations in the intratibial‐injected 5TGM1 MM‐KaLwRij syngeneic murine model of MMBD, in which XRK3F2 induced new cortical bone formation in MM‐injected limbs . Collectively, these data argue for the importance of the p62‐ZZ‐domain‐Gfi1 axis in converging the extracellular myeloma signals to HDAC1/EZH2‐mediated epigenetic gene silencing in MM‐BMSC.…”

Section: Chromatin Alterations In Mm‐exposed Bmscssupporting

confidence: 81%

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

2019

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Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Authenticated OPM2, MM1.S and JJN3 cell lines were provided by Dr. G. David Roodman (18) in 2014(IUSM, Indianapolis, IN). BM aspirates of myeloma patients were kindly provided by Dr. Rebecca Silbermann (IUSM, Indianapolis, IN).…”

Section: Methodsmentioning

confidence: 99%

Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

Mohammad

et al. 2016

Cancer Research

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Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment.

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Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

Cited by 46 publications

References 31 publications

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma

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