ArticleNeoplasia (New York, N.Y.)2025
Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition.
Article in Neoplasia (New York, N.Y.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Review
- An EZH2-SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis.Nature cell biology · 2026Article
- Sterol regulatory element‑binding proteins: Master regulators of lipid metabolic reprogramming in cancer and emerging therapeutic targets (Review).Oncology reports · 2026Review
- Epigenetic dysregulation of B‑cells in autoimmune diseases and lymphomas (Review).International journal of molecular medicine · 2026Review
- Cholesterol in hematological malignancies: metabolism, mechanisms, and clinical implications.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
16 authors.
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No grant is acknowledged in the PubMed record.
Abstract
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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