Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation

Wang, Jingjing; Zhu, Xu; Dang, Lin; Jiang, Hongmei; Xie, Ying; Li, Xin; Guo, Jing; Wang, Yixuan; Peng, Ziyi; Wang, Mengqi; Wang, Sheng; Li, Qian; Wang, Yafei; Wang, Qiang; Ye, Lingqun; Zhang, Lirong; Liu, Zhiqiang

doi:10.1172/jci149526

Cited by 15 publications

(13 citation statements)

References 45 publications

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“…Immuno uorescence assay also validated that hypoxia promoted the accumulation of SRC-3 in the nucleus (Fig 2A , 2B). Similarly, high SRC-3 level was also found in our previously established bortezomib-resistant (BR) MM.1S and LP-1 cells compared with their parental cells (Fig 2C , 2D), 19,22 and administration of a newly developed small molecule targeting SRC-3, the SI-2, 23 partially rescued the sensitivity to BTZ of MM cells under hypoxia condition (Fig 2E , 2F). Importantly, combination of SI-2 and BTZ only showed synergistic anti-MM effect under hypoxia condition, but not in the normoxia controls, as evidenced by the remarkably augmented apoptotic cell rate and cleavage of PARP as a marker of cell apoptosis (Fig 2G , 2H).…”

Section: Hypoxia Upregulates Src-3 Level In MM Cellssupporting

confidence: 72%

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Guo

Wang

et al. 2022

Oncogene

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The bone marrow microenvironment where multiple myeloma (MM) originated is hypoxic and an important stimulus for initiation of drug resistance to chemotherapies, but the underlying mechanisms and key regulators are still indistinct. In the current study, we found that hypoxia stimulus easily induced chemoresistance to proteasome inhibitors (PIs) but not to other chemicals, and the steroid receptor coactivator 3 (SRC-3) expression was remarkably augmented at posttranslational level. Protein interactome analysis identi ed SENP1 as a key modi er of SRC-3 stability, as deSUMOylation by SENP1 attenuated the K11-linked polyubiquitination of SRC-3. Depletion of SENP1 in MM cells by CRISPR/cas9 sgRNA, or in SENP1 / CD19 Cre/+ B cells, accelerated the degradation of SRC-3, and overcame the resistance to PIs at vast scale, which phenotype was similar to administration of SENP1inhibitor Momordin Ιc (Mc) in the Vk*Myc and 5TGM1 mouse models and patient derived xenograft (PDX) of myeloma. Importantly, SENP1 level was positively correlated with SRC-3 level in the tissues from refractory/relapsed MM, as well as in xenograft tissues from mice treated with bortezomib and Mc. Taken together, our ndings suggest that hypoxia induced SENP1 is a crucial regulator of chemoresistance to PIs, and shed light on developing therapeutic strategies to overcome chemoresistance by using small molecules targeting SENP1 or SRC-3.

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Section: Hypoxia Upregulates Src-3 Level In MM Cellssupporting

confidence: 72%

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Guo

Wang

et al. 2022

Oncogene

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“…Nevertheless, our previously established BTZ-resistant MM (BR-MM) cells (Fig. s1E) [21], cultured in the absence of BMSCs, did not exhibit increased sensitivity to RSL3 (Fig. s1F).…”

Section: Bmscs Shift MM Cells Response From Resistance To Ferroptosis...mentioning

confidence: 86%

Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma

Jiang,

Wang,

Zhang

et al. 2024

Oncogene

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Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.

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“…Most recent study by Liu et al. suggested that mdig is recruited by H3K36me2/3 binding protein HDGFL2 (HRP2) for the demethylation H3K27me3 in multiple myeloma cells ( Wang et al., 2022 ). It is interesting that a notable increment of H3K36me3, an epigenetic marker for transcriptional elongation, is observed in the mdig KO cells, suggesting an antagonistic role of mdig on H3K36me3.…”

Section: Discussionmentioning

confidence: 99%

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

Thakur¹,

Qiu²,

Zhang³

et al. 2022

iScience

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Epigenomic reprogramming via HRP2-MINA dictates response to proteasome inhibitors in multiple myeloma with t(4;14) translocation

Cited by 15 publications

References 45 publications

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma

Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma

Deletion of mdig enhances H3K36me3 and metastatic potential of the triple negative breast cancer cells

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