1. G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor–mediated cell death
- Author
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Julie Devin, Philip Vlummens, Eva De Smedt, Nicolas Robert, Elke De Bruyne, Laure Vincent, Guilhem Requirand, Ken Maes, Catharina Muylaert, Guillaume Cartron, Jérôme Moreaux, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Medical Genetics, and Hematology
- Subjects
EXPRESSION ,0301 basic medicine ,Programmed cell death ,G9a ,[SDV]Life Sciences [q-bio] ,GLP ,Apoptosis ,EPIGENOME ,PATHWAY ,histone methyltransferases ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,THERAPEUTIC STRATEGY ,Autophagy ,Medicine and Health Sciences ,C-MYC ,medicine ,Animals ,Humans ,Multiple myeloma (MM) ,PI3K/AKT/mTOR pathway ,Lymphoid Neoplasia ,COMPLEX ,Cell Death ,Bortezomib ,Cell growth ,business.industry ,Biology and Life Sciences ,Histone-Lysine N-Methyltransferase ,Hematology ,Carfilzomib ,3. Good health ,HISTONE METHYLTRANSFERASE ,proteasome ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Histone methyltransferase ,Cancer research ,Proteasome inhibitor ,Multiple Myeloma ,business ,Proteasome Inhibitors ,medicine.drug - Abstract
Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that 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 RNA levels are associated with a worse disease outcome 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 cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly 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. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.
- Published
- 2021