Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition

•GCB-DLBCL insensitive to EZH2 inhibition become dependent on cholesterol synthesis.•This dependency relates to altered LDLR subcellular localization and LDL uptake.•EZH2 inhibition attenuates activation of SREBP2 targets. The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center...

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Published in:Neoplasia (New York, N.Y.) Vol. 70; p. 101243
Main Authors: Niccolai, Rachele, Göbel, Camiel, Ndoj, Klevis, Kreft, Maaike, Kuiken, Hendrik J., Lieftink, Cor, Morris, Ben, Yska, Sietse D., Hendrix, Sebastian, van den Broek, Bram, Pappalardo, Vincent, Kersten, Marie José, Beijersbergen, Roderick L., Zelcer, Noam, van Leeuwen, Fred, Jacobs, Heinz
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.12.2025
Elsevier
Subjects:
Animals
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cholesterol - biosynthesis
CRISPR-Cas9 screen
Diffuse large B cell lymphoma
Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein - genetics
Enhancer of Zeste Homolog 2 Protein - metabolism
EZH2
Humans
LDL-receptor
Lymphoma, Large B-Cell, Diffuse - drug therapy
Lymphoma, Large B-Cell, Diffuse - genetics
Lymphoma, Large B-Cell, Diffuse - metabolism
Lymphoma, Large B-Cell, Diffuse - pathology
Mice
Oncology
Receptors, LDL - metabolism
Xenograft Model Antitumor Assays
Diffuse large B cell lymphoma
Cholesterol Biosynthesis
LDL-receptor
CRISPR-Cas9 screen
EZH2
ISSN:1476-5586, 1476-5586
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Summary:•GCB-DLBCL insensitive to EZH2 inhibition become dependent on cholesterol synthesis.•This dependency relates to altered LDLR subcellular localization and LDL uptake.•EZH2 inhibition attenuates activation of SREBP2 targets. The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.
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ISSN:1476-5586
1476-5586
DOI:10.1016/j.neo.2025.101243