Targeting SREBP2 in cancer progression: Molecular mechanisms, oncogenic crosstalk, and therapeutic interventions

Cholesterol, an essential membrane component and a precursor for steroid hormones and bile acids, plays a vital role in various cellular processes. Cancer cells, in particular, exhibit a heightened demand for cholesterol to support their proliferation. This increased cholesterol requirement can be attributed to the upregulation of cholesterol biosynthesis or enhanced cholesterol uptake. Metabolic reprogramming in cancer cells allows them to sustain the energy demands associated with their aberrant growth characteristics. In normal cells, cholesterol uptake and synthesis are tightly regulated through various mechanisms within the cholesterol metabolism pathway. SREBP2 (Sterol Regulatory Element Binding Protein 2) is a critical master regulator of cholesterol homeostasis in normal cells. Dysregulation of cholesterol metabolism is intricately linked with the development of malignant phenotypes. Furthermore, emerging evidence highlights the crosstalk between SREBP2 and aberrant signaling pathways, such as PI3K/AKT/mTORC1, p53, TGF-β, c-Myc, Hippo, and FoxM1, which promote tumorigenesis. Understanding these molecular interactions between SREBP2 and signaling pathways is crucial for unraveling the mechanisms underlying cancer development. Identifying combinatorial treatment strategies targeting cholesterol metabolism holds great promise in deciphering mechanistic insights into metabolic vulnerabilities in cancer cells. Such strategies have the potential to enhance the efficacy of standard chemo/radiotherapy approaches for highly resistant cancer types. This review explores the regulation of SREBP2 in cancer and elucidates its role in dysregulated cholesterol metabolism. A detailed discussion on the implications of targeting cholesterol metabolism as a therapeutic approach for cancer treatment has also been elucidated.