Project 1

A specific focus of the work of the division is the analysis of processes regulating lipid metabolism downstream of the sterol regulatory element binding proteins (SREBP1 and SREBP2). We have previously shown that SREBPs are activated by oncogenic signaling via the Akt/mTORC1 axis and cooperate with Myc to promote cell growth and survival (Porstmann et al., Cell Metabolism 2008; Gouw et al., Cell Metabolism 2019). Furthermore, we found that SREBP1 promotes de novo fatty acid synthesis and desaturation to prevent lipotoxicity and ER-stress (Grifiths et al., Cancer Metab 2013, Triki et al., Cell Reports 2020). Induction of lipotoxicity by LXRa activation and Raf inhibition was recently identified as a vulnerability in liver cancer (Rudalska et al., Nature Cancer 2021) and inhibition of fatty acid synthesis induces differentiation in neuroblastoma (Ruiz-Perez et al., iScience 2021). 

Our work also uncovered several mechanisms by which oncogenic signaling pathways regulate SREBP to drive essential metabolic processes in cancer cells. Using isogenic colorectal cancer cell lines cultured in 3-dimensional spheroid and organoid cultures as well as xenograft tumors, we found that p53-deficient cells induce SREBP2 via a GSK3-dependent post-translational mechanism. This leads to increased MVP activity and promotes the synthesis of CoQ₁₀, an essential electron transfer molecule located in the mitochondrial membrane. MVP inhibition by statins blocked pyrimidine synthesis and induced oxidative stress and apoptosis in p53-deficient cancer cells in spheroid culture and tumor organoids (Kaymak et al., Cancer Research 2020).

In a second study, we identified SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cell carcinoma (SCC). Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. USP28 binds to mature SREBP2, leading to its de-ubiquitination and stabilization. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung SCC (LSCC) and CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumor growth in a KRas/p53/LKB1 (KPL) mutant mouse model of lung cancer. Furthermore, we found that statins synergize with a dual USP28/25 inhibitor to reduce the viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas (Maier et al., CDD 2023).

We also identified squalene epoxidase (SQLE), a rate-limiting enzyme of cholesterol biosynthesis, as an important driver of androgen independence in PCa. We found that SQLE is a target of miR-205, which is significantly downregulated in advanced PCa. In contrast, SQLE expression is upregulated in advanced PCa and correlates with poor survival in a cohort of high risk PCa patients. Overexpression or CRISPR/Cas-mediated knockout of miR-205 regulates SQLE expression and cell viability in PCa cell lines, including cells resistant to abiraterone and enzalutamide, two second line therapeutics for advanced PCa. Restoration of miR-205 expression or inhibition of SQLE led to inhibition of cholesterol biosynthesis and blocked transactivation of an AR responsive promoter in PCa cells. Furthermore, terbinafine, an antifungal inhibitor of SQLE, efficiently blocked tumor growth in an orthotopic mouse model and prevented biochemical progression in three patients with advanced PCa. These results highlight SQLE as an innovative therapeutic target for the treatment of advanced PCa (Kalogirou et al., Nat Commun 2021).

Together, these results have expanded the current understanding of the regulation of lipid metabolism in cancer and revealed how different metabolic outputs of the mevalonate pathway contribute to cancer relevant processes.

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