Fig. 6: The ZMYND8-c-Myc axis alters glycerophospholipid metabolism in resistant HER2+ breast cancer via induction of cPLA2α.

a Heatmap of glycerophospholipid species in BT474T (n = 10), HR6 (n = 10), ZMYND8 KO1 HR6 (n = 5), ZMYND8 KO2 HR6 (n = 5), c-Myc KO1 HR6 (n = 5), c-Myc KO2 HR6 (n = 5), cPLA2α KO1 HR6 (n = 5), and cPLA2α KO2 HR6 cells (n = 5). b Heatmap of expression of metabolic genes involved in glycerophospholipids in BT474T, HR6, ZMYND8 KO1 HR6, and ZMYND8 KO2 HR6 cells (n = 2). c RT-qPCR analysis of PLA2G3, PLA2G4A, PLAAT3, and PLA2G4F mRNAs in BT474T, HR6, ZMYND8 KO1 HR6, and ZMYND8 KO2 HR6 cells (n = 3). d Analysis of PLA2G4A mRNA expression in human HER2+ breast tumors before and after HER2-targeted therapy from the PAMELA clinical trial. e Immunoblot analysis of ZMYND8 and cPLA2α in BT474T, HR6, ZMYND8 KO1 HR6, and ZMYND8 KO2 HR6 cells (n = 3). f RT-qPCR analysis of PLA2G4A, ZMYND8 and MYC mRNAs in parental, c-Myc KO1, and c-Myc KO2 HR6 cells (n = 3). g Immunoblot analysis of c-Myc and cPLA2α in parental, c-Myc KO1, and c-Myc KO2 HR6 cells (n = 3). h Immunoblot analysis of ZMYND8, c-Myc, and cPLA2α in parental, ZMYND8 KO1, and ZMYND8 KO1+c-Myc HR6 cells (n = 3). i Nucleotide sequence of the c-Myc binding element (in red) at the promoter of the PLA2G4A gene. j ChIP-qPCR assay with anti-c-Myc antibody or IgG in HR6 cells (n = 3). k Genome browser snapshot of ZMYND8 ChIP-seq in MDA-MB-231 cells (GSE108833). rep, replicate. l Heatmap of glycerophospholipid species in tumor organoids-1 treated with vehicle or CDIBA for 6 days (n = 5). Data from biological replicates represent mean ± SEM. P-value was determined by one-way ANOVA with Dunnett’s test (c and f), paired 2-tailed Student’s t-test (d), or unpaired 2-tailed Student’s t-test (j). Source data are provided as a Source Data file.