1. Academic Validation
  2. Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas

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

  • Blood. 2022 Jan 6;139(1):73-86. doi: 10.1182/blood.2021012327.
Yajie Shen 1 2 Jingqi Zhou 3 Kui Nie 4 Shuhua Cheng 4 Zhengming Chen 5 Wenhan Wang 1 Weiqing Wei 1 Daiji Jiang 1 Zijing Peng 1 Yizhuo Ren 1 Yirong Zhang 1 6 Qiuju Fan 1 Kristy L Richards 7 Yitao Qi 2 Jinke Cheng 1 Wayne Tam 4 Jiao Ma 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 2 Department of Biological Science, Shaanxi Normal University School of Life Science, Xi'an, China.
  • 3 School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 Department of Pathology and Laboratory Medicine.
  • 5 Departement of Population Health Sciences, Weill Cornell Medicine, New York, NY.
  • 6 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and.
  • 7 Department of Medicine, Weill Cornell Medicine, New York, NY.
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 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.

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