Histone methyltransferase NSD2 activates PKCα to drive metabolic reprogramming and lenalidomide resistance in multiple myeloma.
Cancer research(2023)
摘要
Multiple myeloma (MM) cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2. Here, we identified PKCα as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA-sequencing of t(4;14) MM cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. Additionally, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production. Metabolomics analysis indicated lactate as a differential metabolite associated with PKCα. As a result, PKCα conferred resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Clinically, t(4;14) MM patients had elevated plasma lactate levels and did not benefit from lenalidomide-based regimens. Altogether, this study provides insights into the epigenetic-metabolism crosstalk in MM and highlights the opportunity for therapeutic intervention that leverages the distinct metabolic program in t(4;14) myeloma.
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关键词
histone methyltransferase,multiple myeloma,lenalidomide resistance,pkcα
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