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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Vydané v:	Neoplasia (New York, N.Y.) Ročník 70; s. 101243
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Elsevier Inc 01.12.2025 Elsevier
Predmet:	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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Abstract	•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.
AbstractList	Highlights•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. •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. 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.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. 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.
ArticleNumber	101243
Author	Yska, Sietse D. Kuiken, Hendrik J. Kersten, Marie José Morris, Ben Pappalardo, Vincent Beijersbergen, Roderick L. Göbel, Camiel van den Broek, Bram Zelcer, Noam Hendrix, Sebastian Kreft, Maaike Jacobs, Heinz Niccolai, Rachele Ndoj, Klevis van Leeuwen, Fred Lieftink, Cor
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Keywords	Diffuse large B cell lymphoma Cholesterol Biosynthesis LDL-receptor CRISPR-Cas9 screen EZH2
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Snippet	•GCB-DLBCL insensitive to EZH2 inhibition become dependent on cholesterol synthesis.•This dependency relates to altered LDLR subcellular localization and LDL... Highlights•GCB-DLBCL insensitive to EZH2 inhibition become dependent on cholesterol synthesis. •This dependency relates to altered LDLR subcellular... The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and...
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SubjectTerms	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
Title	Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition
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