Urothelial-lineage master transcription factor hub proteomics shows mechanisms impeding urothelial cancer cell differentiation
Schuerger, C.; Biswas, S.; Ng, K. P.; Cardone, L.; Gu, X.; Ganguly, S.; Tohme, R.; Durmaz, A.; Stich, M.; Lindner, D. J.; Jha, B.; Mian, O. Y.; Saunthararajah, Y.
Show abstract
Urothelial cancer (UC) cells of the luminal subtype exhibit partial, incomplete differentiation towards umbrella cells that line bladder lumen, seen by morphology and gene expression. Differentiation is stalled even though the cells express master transcription factors (MTFs) that drive luminal urothelial differentiation, e.g., FOXA1 and CEBPB, at levels seen in normal differentiated urothelium. We therefore analyzed the FOXA1/CEBPB MTF hub by mass spectrometry. SWI/SNF coactivator complex (CoA) components, e.g., SMARCA4, ARID1A, that read the epigenetic activation mark histone 3 lysine 27 acetylation (H3K27ac) and use ATP-hydrolysis to open chromatin, were the most abundant proteins pulled-down with FOXA1/CEBPB. However, genes for these and other CoA, e.g., CREBBP, EP300 that write H3K27ac, were mutated/deleted in >95% of UCs in clinical series. Also contained in the hub were corepressors (CoR) that erase H3K27ac and close chromatin, e.g., HDAC1, CHD4 - genes for these CoR were recurrently gained in UCs. Chromatin analyses showed H3K27ac-centered remodeling was needed to activate umbrella but not constitutively accessible cell growth/division/housekeeping genes. Restoring ARID1A into ARID1A-mutated UC cells using lentiviral transduction, or inhibiting CoR with siRNA or small molecules, activated umbrella genes and terminated replications. In summary, UC-genesis selects for loss- and gain-of-function of CoA and CoR respectively in the urothelial-lineage MTF hub; small molecule CoR-inhibitors are candidate remedies to renew maturation towards terminal differentiated-fates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744501v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@19e853org.highwire.dtl.DTLVardef@e3c934org.highwire.dtl.DTLVardef@ae7874org.highwire.dtl.DTLVardef@66331b_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube 92%
- Integrated epigenome, exome and transcriptome analyses reveal molecular subtypes and homeotic transformation in uterine fibroids. 91%
- Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer 91%
Similar papers in this journal
- Pparg drives luminal differentiation and luminal tumor formation in the urothelium 92%
- Multiomic analysis reveals cellular and epigenetic plasticity in intestinal pouches of ulcerative colitis patients 92%
- Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma 92%
Similar papers in this journal
- An atlas of cell types in the mammalian epididymis and vas deferens 91%
- FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy 90%
- Mixed ancestry analysis of whole-genome sequencing reveals common, rare, and structural variants associated with posterior urethral valves 90%
Similar papers in this journal
- RNF185 control of COL3A1 expression limits prostate cancer migration and metastatic potential. 90%
- GFI1 cooperates with IKAROS/IKZF1 to activate gene expression in T-cell acute lymphoblastic leukemia 89%
- Archetype analysis of lung adenocarcinoma premalignancy links heterogeneity in premalignant lesions to diverging features of invasive disease 89%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.