Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC.
Humans
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Proto-Oncogene Proteins c-myc
/ metabolism
Signal Transduction
/ drug effects
NF-kappa B
/ metabolism
Cell Line, Tumor
Lymphoma, Large B-Cell, Diffuse
/ metabolism
Gene Expression Regulation, Neoplastic
/ drug effects
Apoptosis
/ drug effects
Bromodomain Containing Proteins
Proteins
Minor Histocompatibility Antigens
Apoptosis
BCL2-proteins
BCL2A1
BETi
Epigenetics
Lymphoma
PROTACs
c-MYC
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
received:
25
04
2024
accepted:
06
08
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
epublish
Résumé
The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL.
Identifiants
pubmed: 39192247
doi: 10.1186/s12964-024-01782-9
pii: 10.1186/s12964-024-01782-9
doi:
Substances chimiques
Proto-Oncogene Proteins c-bcl-2
0
Proto-Oncogene Proteins c-myc
0
NF-kappa B
0
BCL2-related protein A1
0
bromodomain and extra-terminal domain protein, human
0
MYC protein, human
0
Bromodomain Containing Proteins
0
Proteins
0
Minor Histocompatibility Antigens
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
415Informations de copyright
© 2024. The Author(s).
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