Radiation induces p53 -dependent cell apoptosis in bladder cancer cells with wild-type- p53 but not in p53 -mutated bladder cancer cells

SummaryInhibition of the endolysosomal cation channel, TRPML1, which is encoded by MCOLN1, deters the proliferation of cancer cells with augmented TFEB activity. Here, we report that the tumor suppressor, p53, antagonizes TFEB-driven MCOLN1 expression in bladder cancer. Not only was the constitutive loss of p53 in bladder cancer cells associated with higher MCOLN1 mRNA, knockdown of TP53 in lines with wild type alleles of the tumor suppressor increased MCOLN1 expression. Elevated TRPML1 abundance in p53-deficient cancer cells, although not sufficient for bolstering proliferation, was necessary for the effects of oncogenic HRAS on cell division, cytokine production, and invasion. These data demonstrate that hyperactivation of the TFEB– MCOLN1 transcriptional axis in urothelial cells lacking p53 permits tumorigenesis stemming from HRAS mutations. Furthermore, the insight that loss of p53 predicts addiction to TRPML1 informs an actionable therapeutic strategy for bladder cancer.

Download Full-text

Effect of Yes Associated Protein 1 Silence on Proliferation and Apoptosis of Bladder Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2637 ◽

2021 ◽

Vol 11 (5) ◽

pp. 857-863

Author(s):

Gaoliang Wu ◽

Chao Hao ◽

Xueliang Qi ◽

Jianqiang Nie

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Bladder Cancer ◽

Cancer Cells ◽

Cell Apoptosis ◽

Direct Role ◽

Cycle Arrest ◽

Proliferation And Apoptosis ◽

Bladder Cancer Cells ◽

Cancer Tissues

Yes Associated Protein 1 (YAP) can act as either an oncoprotein or a tumor suppressor in different cellular contexts. However, the reports about the direct role of YAP silence in bladder cancer cells are rare. We designed loss-off-function experiments to investigate the effect of YAP knockdown on bladder cancer cell proliferation, cell cycle and cell apoptosis. We examined YAP expression in human bladder cancer and paracancerous tissues using RT-qPCR, western blot and immunohisto-chemistry. YAP short hairpin RNA (shRNA) was successfully constructed and transfected into T24 cells to knockdown YAP. Cell proliferation, cell cycle and cell apoptosis were analyzed by CCK-8 and flow cytometry. We found the expression levels of YAP mRNA and protein were significantly increased in the bladder cancer tissues when compared with that in the paracancerous tissues. shRNA YAP inhibited cell proliferation, induced cell cycle arrest at G1 phase, and induced cell apoptosis. In conclusion, our findings provided the first evidence that YAP knockdown could inhibit cell proliferation and induce cell apoptosis of bladder cancer cells. YAP inhibition may be beneficial in the treatment of bladder cancer.

Download Full-text

ARID1A-mutant and deficient bladder cancer is sensitive to EZH2 pharmacologic inhibition

10.1101/2021.01.12.426383 ◽

2021 ◽

Author(s):

James E. Ferguson ◽

Hasibur Rehman ◽

Darshan S. Chandrashekar ◽

Balabhadrapatruni V. S. K. Chakravarthi ◽

Saroj Nepal ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Wild Type ◽

Driver Genes ◽

Specific Subset ◽

Bladder Cancer Cells ◽

Metastatic Urothelial Carcinoma ◽

Carcinoma Of The Bladder

AbstractMetastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly 20% of early and late stage tumors. EZH2 is a histone methyltransferase that acts as an oncogene. The data herein show that ARID1A deficient tumors, but not ARID1A wild-type tumors are sensitive to EZH2 inhibition. Specifically, EZH2 inhibitor-treated ARID1A deficient bladder cancer cells show significantly reduced cell viability, colony formation, and in vivo tumor growth relative to ARID1A-wild type bladder cancer cells. Thus, our study suggests that a specific subset of bladder cancer patients with ARID1A mutations can be therapeutically treated with pharmacologic inhibitors targeting EZH2.

Download Full-text