TAp63-regulated microRNAs suppress cutaneous squamous cell carcinoma through inhibition of a network of cell cycle genes

Membrane lipids play important roles in the regulation of cell fate, including the execution of ferroptosis. Ferroptosis is a non-apoptotic cell death mechanism defined by iron-dependent membrane lipid peroxidation. Phospholipids containing polyunsaturated fatty acids (PUFAs) are highly vulnerable to peroxidation and are essential for ferroptosis execution. By contrast, the incorporation of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis.The enzymes and pathways that govern PUFA and MUFA metabolism therefore play a critical role in determining cellular sensitivity to ferroptosis. Here, we review three lipid metabolic processes-fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling-that can govern ferroptosis sensitivity by regulating the balance of PUFAs and MUFAs in membrane phospholipids.

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Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR results in conservation of intracellular glutathione, limiting the accumulation of toxic lipid peroxides and preventing the onset of ferroptosis in response to cystine deprivation. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.

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Platinum (Pt) compounds such as oxaliplatin are amongst the most commonly prescribed anti-cancer drugs. Despite their considerable clinical impact, the molecular basis of platinum cytotoxicity and cancer specificity remain unclear. Here, we show that oxaliplatin, a backbone for the treatment of colorectal cancer, causes liquid-liquid demixing of nucleoli at clinically-relevant concentrations by interfering with the interaction networks that organize nucleoli. This biophysical defect leads to cell cycle arrest, impaired rRNA processing and shutdown of PolI-mediated transcription, ultimately resulting in cell death. We propose that the mechanism of action of oxaliplatin provides a blueprint for the therapeutic targeting of the increasing number of cellular processes being linked to biomolecular condensates.

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<p>Supplementary Table 1: Differentially expressed genes in TAp63-/- cuSCC vs. TAp63-/- skin Supplementary Table 2: Differentially expressed miRNAs in TAp63-/- cuSCC vs. TAp63-/- skin Supplementary Table 3: microRNA-mRNA pair analysis of TAp63-/- cuSCC vs. TAp63-/- skin: Underexpressed miRNAs and overexpressed mRNAs. Supplementary Table 4: microRNA-mRNA pair analysis of TAp63-/- cuSCC vs. TAp63-/- skin: Overexpressed miRNAs and underexpressed mRNAs. Supplementary Table 5: Differentially expressed mRNAs from TAp63-/- cuSCC vs cuSCC and Human cuSCC vs. skin. Supplementary Table 6: Differentially expressed miRNAs from TAp63-/- cuSCC vs cuSCC and Human cuSCC vs. skin. Supplementary Table 7: GSEA of common differentially expressed mRNAs in TAp63-/- cuSCC and human cuSCC. Supplementary Table 8: Differentially expressed proteins in miR-30c-2* mimic transfected COLO16 cells measured by TMT-6-plex LC-MS/MS. Supplementary Table 9: Differentially expressed proteins in miR-497 mimic transfected COLO16 cells measured by TMT-6-plex LC-MS/MS. Supplementary Table 10: miRNA target prediction of corresponding mRNAs for the differentially expressed proteins in the miR-30c-2* transfected COLO16 cells. Supplementary Table 11: miRNA target prediction of corresponding mRNAs for the differentially expressed proteins in the miR-497 transfected COLO16 cells. Supplementary Table 12: Overexpressed mRNAs in both mouse TAp63-/- cuSCC and human cuSCC RNA-Seq signatures</p>