| Title | GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer |
| Authors | Guo, Yanxia Yuan, Xiaotian Li, Kailin Dai, Mingkai Zhang, Lu Wu, Yujiao Sun, Chao Chen, Yuan Cheng, Guanghui Liu, Cheng Straat, Klas Kong, Feng Zhao, Shengtian Bjorkholm, Magnus Xu, Dawei |
| Affiliation | Shandong Univ, Dept Urol, Shandong Prov Hosp, Jinan, Peoples R China Key Lab Kidney Regenerat Shandong Prov, Jinan, Peoples R China Karolinsk Inst, Dept Med, Div Hematol, Bioclinicum, Stockholm, Sweden Karolinsk Inst, Ctr Mol Med, Stockholm, Sweden Karolinska Univ Hosp Solna, Stockholm, Sweden Shandong Univ, Sch Med, Jinan, Peoples R China Shandong Univ, Hosp 2, Cent Res Lab, Jinan, Peoples R China Beijing Univ, Hosp 3, Dept Urol, Beijing, Peoples R China Karolinska Inst Shandong Univ Collaborat Labs Can, Jinan, Peoples R China |
| Keywords | TRANSCRIPTION FACTOR GABP TERT PROMOTER MUTATIONS COMPREHENSIVE MOLECULAR CHARACTERIZATION MESSENGER-RNA ETS FAMILY SUBTYPES BIOMARKERS BASAL IDENTIFICATION EXPRESSION |
| Issue Date | Jun-2020 |
| Publisher | CELL DEATH AND DIFFERENTIATION |
| Abstract | TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures. Luminal tumors express higher GABPA than do basal ones. Lower GABPA expression is associated with the GABPA gene methylation or deletion (especially in basal subtype of BC tumors), and predicted significantly shorter patient survival based on TCGA and our cohort of BC patient analyses. Taken together, GABPA dictates luminal identity of BC cells and inhibits aggressive diseases in BC by promoting cellular differentiation despite its stimulatory effect on telomerase/TERT activation. Given these biological functions and its frequent methylation and/or deletion, GABPA serves as a tumor suppressor rather than oncogenic factor in BC. The GABPA effect on oncogenesis is context-dependent and its targeting for telomerase inhibition in BC may promote disease metastasizing. |
| URI | http://hdl.handle.net/20.500.11897/589170 |
| ISSN | 1350-9047 |
| DOI | 10.1038/s41418-019-0466-7 |
| Indexed | SCI(E) |
| Appears in Collections: | 第三医院 |
