Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma.
Yinyin XuJing GuoJing LiuYing XieXin LiHongmei JiangJingjing WangZiyi PengJingya WangSheng WangChao WanLanting ChenYuping ZhongBei-Zhong LiuZhiqiang LiuPublished in: Oncogene (2021)
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.
Keyphrases
- multiple myeloma
- induced apoptosis
- binding protein
- cell cycle arrest
- poor prognosis
- endothelial cells
- newly diagnosed
- gene expression
- dna methylation
- bone mineral density
- genome wide
- clinical trial
- cell death
- endoplasmic reticulum stress
- signaling pathway
- cancer therapy
- long non coding rna
- small molecule
- soft tissue
- physical activity
- drug delivery
- high glucose
- diabetic rats
- protein kinase
- copy number
- replacement therapy
- drug release