HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
| Autor: | John K. Eaton, Yilong Zou, Paul A. Clemons, Michael J. Palte, Yuen-Yi Tseng, Rebecca Deasy, Maria Alimova, Wenyu Wang, Elizaveta S. Leshchiner, Jesse S. Boehm, John G. Doench, Stuart L. Schreiber, Bridget K. Wagner, Clary B. Clish, Vasanthi S. Viswanathan, Toni K. Choueiri, Amy Deik, Haoxin Li, Vlado Dančík, Sabina Signoretti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Kidney Ferroptosis Flippase Biology medicine.disease GPX4 3. Good health 03 medical and health sciences Clear cell renal cell carcinoma 0302 clinical medicine medicine.anatomical_structure Renal cell carcinoma 030220 oncology & carcinogenesis Membrane topology medicine Cancer research CRISPR lipids (amino acids peptides and proteins) 030304 developmental biology |
| DOI: | 10.1101/388041 |
| Popis: | SUMMARYKidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2α–HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1β–1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.HIGHLIGHTSccRCC cells exhibit strong susceptibility to GPX4 inhibition-induced ferroptosisThe GPX4-dependent and ferroptosis-susceptible state in ccRCC is associated with PUFA-lipid abundanceThe HIF-2α–HILPDA axis promotes the selective deposition of PUFA-lipids and ferroptosis susceptibilityAGPAT3 selectively synthesizes PUFA-phospholipids and primes renal cells for ferroptosis |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|