Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 ⁺ diffuse large B-cell lymphomas

Abstract

Shen et al studied the stem cell regulatory protein SOX9 in the context of diffuse large B-cell lymphoma (DLBCL), demonstrating that SOX9 positivity correlates with advanced-stage disease and SOX9 silencing decreases lymphoma cell proliferation. Transcriptome analysis identified DHCR24, a critical enzyme for cholesterol biosynthesis, as the target of SOX9, and inhibition of cholesterol synthesis also decreased growth of DLBCL xenografts. This suggests that statins may synergize with chemotherapy in the treatment of DLBCL.

Key Points

• SOX9 plays an oncogenic role in germinal center B-cell type, IGH-BCL2 ⁺ DLBCL, by promoting cell proliferation and inhibiting apoptosis.

• SOX9 drives lymphomagenesis through upregulation of DHCR24, the key final enzyme in the cholesterol biosynthesis pathway.

Visual Abstract

Abstract

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G ₁/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.