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

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.

Hyperbaric Oxygen Therapy Does Not Have a Negative Impact on Bone Signaling Pathways in Humans

“…DKK1 is another important modulator of the Wnt pathway [ 37 ]. Hypoxia seems to modulate the expression of DKK1 [ 38 ], but the effects of hyperoxia have not been studied. In our study, we did not find any evidence of increased levels of sclerostin or DKK1 in patients who were exposed to HBOT.…”

Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers

“…PTMs found on histones include methylation, acetylation and ubiquitination on lysine residues, phosphorylation on serine, threonine, and tyrosine residues and/or citrullination on arginine residues [32]. Histone PTMs are routinely detected through site-specific antibodies, as demonstrated recently by Xu and co-workers [33] investigating histone H3 lysine 36 dimethylation (H3K36me2) levels in myeloma cells under normoxia or hypoxia conditions using Western blotting [33]. By detecting both the protein and site-specific modification abundance levels using precise antibodies, the degree of histone modification can be quantified.…”

Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma

“… 52 Furthermore, the hypoxia‐inducible p38‐CREB‐DKK1 axis and upregulation of HIF‐1α‐inducible MMSET contribute to inhibition of osteoblastic bone formation. 53 These reports indicate that fluid factors released from myeloma and stroma cells exposed to hypoxic stress create a favorable BM microenvironment for myeloma cell survival by regulating their chemotaxis, inhibiting the osteoblasts, and stimulating the osteoclasts and surrounding vascular endothelial cells.…”

“…Osteoclast activation is also an important aspect of the BM microenvironment; interleukin‐32, which is regulated by HIF‐1α, is released from the myeloma cells by extracellular vesicles and taken up by osteoclasts to promote their differentiation 52 . Furthermore, the hypoxia‐inducible p38‐CREB‐DKK1 axis and upregulation of HIF‐1α‐inducible MMSET contribute to inhibition of osteoblastic bone formation 53 . These reports indicate that fluid factors released from myeloma and stroma cells exposed to hypoxic stress create a favorable BM microenvironment for myeloma cell survival by regulating their chemotaxis, inhibiting the osteoblasts, and stimulating the osteoclasts and surrounding vascular endothelial cells.…”