Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma

Xie, Ying; Liu, Jing; Jiang, Hongmei; Wang, Jingya; Li, Xin; Wang, Jingjing; Zhu, Shuai; Guo, Jing; Li, Tao; Zhong, Yuanyuan; Zhang, Qiguo; Liu, Zhiqiang

doi:10.1038/s41388-019-1037-6

Cited by 42 publications

(39 citation statements)

References 30 publications

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“…The International Myeloma Working Group criteria were used to diagnose patients with MM [35], and the key exclusion criteria were adopted accordingly [36]. Bone marrow specimens were taken as aliquots from patients with myeloma for routine examination, and plasma was taken for ELISA assay, both according to our previous procedures [37].…”

Section: Patient Samplesmentioning

confidence: 99%

“…Cell lines and cultures have been described in our previous report [37]. For hypoxia induction, MM cells were placed in a hypoxic chamber (Coy Laboratory Products, Grass Lake, MI, USA) and gassed with 95% N 2 /5% CO 2 at 37°C for different durations.…”

Section: Cell Linesmentioning

confidence: 99%

“…Normoxia and hypoxia myeloma cells RNA was isolated using Trizol (Ambion, Carlsbad, CA, USA) according to the manufacturer's instructions. Details of qPCR and western blot procedures can be found in our previous report [37]. The primers used in qPCR and antibodies used in this study are listed in Supplementary Table 1.…”

Section: Real-time Pcr and Western Blot Assaysmentioning

confidence: 99%

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Guo

Liu

et al. 2021

Oncogene

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Myeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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Section: Patient Samplesmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

Section: Real-time Pcr and Western Blot Assaysmentioning

confidence: 99%

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Guo

Liu

et al. 2021

Oncogene

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“…Moreover, the combination eliminates cancer stem‐like cell characteristics from the bulk cell population, though BTZ treatment alone produced a rise in CSC characteristics. Previous studies found that stem‐like tumour cells are resistant to the direct cytotoxic effects of BTZ, and this BTZ resistance enriches genes of stemness 7,9 . The mechanism behind this acquired resistance is still unexplored, though it is possibly due to the induction of any oncogenic transcription or the cell’s recovery response to evade the BTZ effect that may eventually result in resistance 51–53 .…”

Section: Discussionmentioning

confidence: 99%

“…MM is highly heterogeneous and, despite the availability of advanced therapeutic options (such as the proteasome inhibitor bortezomib or the immunomodulatory drug pomalidomide) which have markedly increased patient overall survival, the majority of myeloma patients relapse eventually. This is probably due to the ineffectiveness of these drugs against cancer stem‐like cells 7–9 . Most likely, the high drug efflux capacity of MMSCs attributes to the drug resistance in myeloma, leading MM a non‐managable fetal malignancy 5 .…”

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confidence: 99%

The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma

Liang

Wang

et al. 2020

Br J Haematol

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Multiple myeloma stem-like cells (MMSCs) are responsible for initiation and relapse, though novel treatment paradigms that effectively eradicate MMSCs are yet to be developed. Selective inhibition of the cell cycle regulatory kinase Wee1 by MK1775 is being explored as a potential anti-cancer therapeutic. We report that higher expression of Wee1 is correlated with poor survival in multiple myeloma (MM). The MM models and patientderived CD138 + plasma cells are particularly sensitive to the growth-inhibitory effects of the Wee1 inhibitor MK1775. MK1775 induces Mus81-Eme1 endonuclease-mediated DNA damage in S-phase cell cycle that results in a blockade of replication and then apoptosis. Furthermore, MK1775 strongly suppresses the features of stemness in vitro, in vivo and in primary CD138 + cells by decreasing ALDH1 + cell fraction and the expression of ALDH1. In addition, co-treatment of MK1775 with bortezomib is synergistic in vitro and in vivo. Bortezomib, although it enhances ALDH1 + cells, when combined with MK1775 abrogates this stimulatory effect on stemness. Considering MM as an invariably incurable malignancy due to the presence of heterogenic myeloma stem-like cells, our study presents inhibition of Wee1 as a promising targeted therapy for MM and provides a compelling rationale to further investigate the activity of MK1775 against myeloma in clinical settings.

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Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Jiang

Wang

et al. 2022

Clinical & Translational Med

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Background t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. Methods An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA‐seq. NSG mouse‐based xenograft model and intra‐bone model were applied to qualify the synergistic effect in vivo. Results We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain‐ and loss‐of‐functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ‐resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP‐1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. Conclusions Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds.

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Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple myeloma

Cited by 42 publications

References 30 publications

Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

The Wee1 kinase inhibitor MK1775 suppresses cell growth, attenuates stemness and synergises with bortezomib in multiple myeloma

Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

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