The KMT1A-GATA3-STAT3 circuit is a novel self-renewal signaling of human bladder cancer stem cells

Purpose: Bladder cancer (BC) is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis and drug-resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs.<br />Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary BC samples #1 and #2, and the BC cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired BC and normal tissues, different tumor cell lines, the public microarray datasets of human BC, and TCGA database were applied for the verification of gene expression.<br />Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710~-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351~-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. Additionally, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors.<br />Conclusions:KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy.

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