Abstract PO-035: SOX4 and SMARCA4 upregulate glycolysis-driven tumor proliferation through Hexokinase 2 in Triple Negative Breast Cancer
Authors: Khanna Pooja , Mehta Gaurav , Bhatt Vrushank , Guo Jessie Y. , Gatza Michael L. 
Published: December 2020

SOX4 is a well-established oncogenic transcription factor and has been shown to be associated with malignant transformation and metastasis in several cancer types including breast, prostate, acute lymphoblastic leukemia, and melanoma. While SOX4 is overexpressed in ~85% of TNBCs (Triple Negative Breast Cancers), the mechanisms by which it contributes to activation of pro-proliferative or pro-survival signaling in these tumors remains unclear. We determined that SOX4 forms a novel and essential complex with the SWI/SNF ATPase SMARCA4 and demonstrated that this complex is required to maintain an open and active chromatin conformation at the promoter and enhancer regions of SOX4-regulated genes. An integrated analysis of ChIPseq and RNAseq data was used to identify SMARCA4-dependent and SMARCA4-independent SOX4 gene expression programs and enrichment analyses indicated that these programs are responsible for unique down-stream signaling networks. SMARCA4-dependent SOX4 signaling was found to be correlate with a poor prognosis in TNBC tumors and was associated with increased cell proliferation and activation of pro-oncogenic processes, including glycolysis. Consistent with these data, in vitro studies showed that SOX4 and SMARCA4 are essential for TNBC breast tumor cell proliferation, survival and colony formation. Mass spectrometry-based metabolomic profiling was used to demonstrate that SOX4 can induce glycolysis as evident by increased glucose-6-phosphate, glyceralehyde-3-phosphate, dihydroxyacetone phosphate, 2-phosphoglycerate, pyruvate and lactate following SOX4 overexpression and the effect of SOX4 and SMARCA4 on glucose consumption was confirmed in vitro. Mechanistically, we determined that SOX4 and SMARCA4 cooperate to transcriptionally regulate expression of Hexokinase 2 (HK2), which catalyzes the first step in glucose metabolism, and that increased expression of HK2 is required to mediate SOX4-dependent glycolysis. Finally we demonstrate that genetic or pharmacological inhibition of HK2 results in reduced TNBC cell proliferation and growth. Collectively, our data suggest that SOX4 and SMARCA4 cooperate to regulate glycolysis and cell proliferation in TNBC in part through activation of HK2 expression. Given the noted association between SOX4 expression and increased tumor proliferation and aggressiveness in multiple forms of cancer, as well as evidence that SOX4 can regulate SMARCA4 expression, these data suggest that aberrant SOX4 activity may have a similar effect on metabolic and cell signaling across multiple tumor types.

Citation Format: Pooja Khanna, Gaurav Mehta, Vrushank Bhatt, Jessie Y. Guo, Michael L. Gatza. SOX4 and SMARCA4 upregulate glycolysis-driven tumor proliferation through Hexokinase 2 in Triple Negative Breast Cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-035.