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

Yinyin Xu,Hongmei Jiang,Ziyi Peng,Jingjing Wang,Jing Liu,Jingya Wang,Yuping Zhong,Sheng Wang,Beizhong Liu,Jing Guo,Lanting Chen,Chao Wan,Zhiqiang Liu,Ying Xie,Xin Li

doi:10.1038/s41388-020-01590-8

Abstract

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.

Highlights

Myeloma bone disease is the most frequent feature of myeloma, occurring in approximately two-thirds of patients
DKK1, ATPbinding cassette subfamily G member 2 (ABCG2), nuclear receptor-binding SET domain protein 2 (NSD2), and BCL2 apoptosis regulator (BCL2), which are closely related to myeloma progression and bone lesions, were included in the highly elevated genes, and activating transcription factor 3 (ATF3), MAX interactor 1, dimerization protein (MXI1), and stanniocalcin 2 (STC2) are known targets of the hypoxia-inducible factor (HIF)-1α signaling pathway (Fig. 1a)
We found a strong positive correlation between DKK1 and MMSET expression in myeloma cells (Fig. 3g), and we observed that DKK1 levels were significantly higher in bone marrow plasma from t(4;14)-positive patients compared with patients with other chromatin abnormalities (Fig. 3h)

Summary

Objectives

This study aimed to identify potential mechanisms responsible for DKK1 overexpression in pathophysiological hypoxic conditions, such as in chemotherapy

Methods

Results

Conclusion