Abstract 2456: 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: July 2021

Triple-negative breast cancer (TNBC) accounts for nearly 1-in-4 breast cancer related deaths in the United States yearly despite representing 10-12% of newly diagnosed cases. This aggressive disease, which is largely synonymous with the basal-like molecular subtype, predominantly affects younger and African American women. Despite recent advances, overall survival has not drastically improved, highlighting the need to identify novel therapeutic opportunities. We determined that the oncogenic transcription factor SOX4 is overexpressed in ~88.1% of basal-like tumors relative to adjacent normal tissue. Immunoprecipitation follow by MS was identified the SWI/SNF ATPase SMARCA4 as an essential SOX4 cofactor that is concurrently overexpressed in basal-like tumors. Mechanistic studies showed that this complex is required to maintain an active open chromatin conformation at regulatory regions upstream of SOX4-regulated genes. To identify the functional impact of overexpression in TNBC, RNAseq and ChIPseq analyses were used to identify SMARCA4-dependent and -independent SOX4 gene expression programs. Analyses of 3,000+ tumor samples from the METABRIC and TCGA cohorts was used to investigate the functional and clinical implications of these gene expression programs in human tumors. Investigation of SOX4 and SMARCA4 binding to promoters and subsequent gene transcription identified SMARCA4-dependent down-stream signaling programs associated with overall worse prognosis and key metabolomic processes. This correlation was confirmed in vitro by demonstrating that both SOX4 and SMARCA4 could mediate changes in intracellular glucose consumption. Metabolomic profiling of breast cancer cell lines demonstrated that SOX4 overexpression resulted in increased glycolysis. Mechanistic studies have determined that SOX4/SMARCA4 transcriptionally regulate expression of Hexokinase 2 (HK2) which catalyzes the first step in glucose metabolism, and HK2 activity is essential for SOX4/SMARCA4-regulation of glycolysis. Given that our data demonstrate that SOX4 or SMARCA4 can regulate cell proliferation/survival and that glycolysis has been shown to modulate cell proliferation, we hypothesized that SOX4-SMARCA4 cooperatively regulate the proliferative capacity of TNBC cells through altered glucose consumption. Consistent with this premise, in vitro studies showed that SOX4 and SMARCA4 are essential for breast tumor cell proliferation, survival and colony formation. Importantly, genetic or pharmacological inhibition of HK2 results in reduced TNBC cell proliferation and growth. Collectively these data demonstrate that the SOX4/SMARCA4 complex mediates the proliferative capacity of TNBC cells by modulating metabolic processes. Given the drug-ability of the glycolysis pathway, these results may have important clinical implications for TNBC patient treatment.

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: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2456.