G9a/GLP-targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor mediated cell death

Research output: Contribution to journalArticle

Abstract

Multiple myeloma (MM) is a (epi)genetic highly heterogeneous plasma cell malignancy, which remains
mostly incurable. Deregulated expression and/or genetic defects in epigenetic modifying enzymes
contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a
was reported in several cancers, including MM, correlating with disease progression, metastasis and poor
prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM
biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a
mRNA levels are associated with a worse disease outcome both in newly diagnosed and relapsed MM
patients. G9a/GLP-targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-
phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies
revealed that G9a/GLP-targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1
pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP-targeting are associated with
repressive histone marks. G9a/GLP-targeting sensitizes MM cells to the proteasome inhibitors (PIs)
bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38
and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor
growth and co-treatment with bortezomib resulted in a further reduction in tumor burden and a
significant prolonged survival. In conclusion, we provide evidence that the histone methyltransferases
G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels
and G9a/GLP-targeting represents a promising strategy to improve PI-based treatment in patients with
high G9a/GLP levels.
Original languageEnglish
Pages (from-to)2325-2338
Number of pages14
JournalBlood Advances
Volume5
Issue number9
Publication statusPublished - 24 Feb 2021

Keywords

  • Multiple myeloma (MM)
  • G9a
  • GLP
  • Histone methyltransferases
  • Proteasome inhibitors

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