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Biochemical pharmacology

Biochemical pharmacology

IF: 5.3
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ALKBH5 reverses romidepsin-mediated anti-multiple myeloma activity via regulation of m6A modification of FOXM1

Published:24 May 2025 DOI: 10.1016/j.bcp.2025.116998
Yaxin Zhang , Xu Cao , Wenjing Li , Zeyu Cui , Jiwei Mao , Ruosi Yao , Linlin Liu

Abstract

Multiple myeloma (MM), a prevalent hematological malignancy, is characterized by the abnormal proliferation and accumulation of plasma cells within the bone marrow. ALKBH5, an RNA demethylase, is implicated in various tumor-related processes, yet its role in myeloma remains insufficiently understood. In this study, we revealed that elevated ALKBH5 expression correlates with poor MM prognosis. Furthermore, romidepsin, a recognized histone deacetylase (HDAC) inhibitor, was found to significantly suppress both the protein levels and enzymatic activity of ALKBH5. Interestingly, while ectopic expression of ALKBH5 did not directly influence cell viability, its overexpression mitigated romidepsin-induced apoptosis. Conversely, ALKBH5 knockout enhanced the apoptotic effects of romidepsin, highlighting a potential synergistic interaction. Our findings also demonstrated that ALKBH5 attenuates romidepsin-mediated DNA damage through γH2AX activation. At the mechanistic level, ALKBH5 overexpression reduced m6A methylation of FOXM1 mRNA, stabilizing the transcript and promoting its translation. In contrast, romidepsin increased m6A methylation, accelerating FOXM1 mRNA decay. Notably, reintroduction of ALKBH5 reversed romidepsin’s impact on FOXM1 expression. Additionally, CRISPR/Cas9-mediated ALKBH5 knockout enhanced the synergistic effects of romidepsin by inducing m6A-dependent FOXM1 mRNA destabilization. Our xenograft model further validated that ALKBH5 counteracts romidepsin-induced anti-MM activity by enhancing FOXM1 protein translation. Collectively, these findings illustrate that romidepsin exerts anti-MM effects by impairing ALKBH5 enzymatic activity and promoting FOXM1 mRNA m6A methylation. Therapeutic strategies combining ALKBH5 knockout with romidepsin may offer promising avenues for improving MM treatment outcomes.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone 128517-07-7 C24H36N4O6S2 234 suppliers $28.00-$4766.80
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone 128517-07-7 C24H36N4O6S2 234 suppliers $28.00-$4766.80
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone 128517-07-7 C24H36N4O6S2 234 suppliers $28.00-$4766.80
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone 128517-07-7 C24H36N4O6S2 234 suppliers $28.00-$4766.80

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