Abstract
AbstractAlthough 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 G1/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.
Highlights
Sex-determining region Y box 9 protein (SOX9) is a member of the SOX family of transcription factors, which are developmental regulators that possess high-mobility group (HMG) box DNA binding and transactivation domains.[1]
SOX9 is highly expressed in germinal center B-cell (GCB) subtypes of DLBCL accompanied by IGH-BCL2 mutations
We attempted to look for SOX9 mutations in SOX91DLBCL by Sanger performing Sanger sequencing on 7 cases
Summary
Sex-determining region Y box 9 protein (SOX9) is a member of the SOX family of transcription factors, which are developmental regulators that possess high-mobility group (HMG) box DNA binding and transactivation domains.[1]. SOX9 mutations, most of which are missense, are infrequent and are detected in 1% of tumors overall (https://cancer.sanger.ac.uk/ cosmic/gene/analysis?ln=SOX9). SOX9 mutations are enriched in colorectal cancers and are present in 11% of these tumors.[14] More than 80% of these mutations are frameshift or nonsense mutations that are associated with mutated KRAS and wild-type TP53 status.[14]
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