Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in...

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Epigenetic deregulation is crucial in bladder cancer pathogenesis.
• KDM6A (Lysine (K)-specific demethylase 6A) is frequently mutated in bladder cancer, but its role is unclear.
• Understanding KDM6A's function can lead to novel therapeutic strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms by which KDM6A deficiency drives bladder cancer.
• To investigate the cooperative effect of KDM6A loss and p53 haploinsufficiency in bladder tumorigenesis.
• To identify potential therapeutic targets for KDM6A-mutated bladder cancer.

Main Methods:

• Generation of Kdm6a-deficient mice with p53 haploinsufficiency.
• Induction of bladder tumors using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN).
• Phenotypic, pathologic, molecular, and cellular analyses of isolated urothelia and human bladder cancer samples.

Main Results:

• KDM6A deficiency activated cytokine/chemokine pathways and M2 macrophage polarization.
• KDM6A loss promoted cancer stem cells and cooperated with p53 haploinsufficiency to cause bladder cancer.
• Dual inhibition of IL6 and chemokine (C-C motif) ligand 2 suppressed KDM6A-deficient bladder cancer cell growth.

Conclusions:

• KDM6A deficiency contributes to bladder cancer through inflammatory pathways and stem cell enrichment.
• Findings offer insights into bladder cancer multistep carcinogenesis.
• Targeting IL6 and chemokines presents a potential therapeutic approach for KDM6A-dysfunctional bladder cancer.