G9a Inhibition Has Antitumor Activity in Bladder Cancer

There are limited established therapies for bladder cancer, which can be lethal if it reaches advanced stages and invades surrounding muscle tissue. Segovia, San José-Enériz, Munera-Maravilla, and colleagues found that expression of the histone methyltransferase G9a, suggested in prior studies to be a bladder cancer oncoprotein, was higher in human non–muscle-invasive bladder cancer tumors than in adjacent healthy tissue, and higher levels of the G9a mRNA and protein were correlated with increased chance of bladder cancer recurrence. CM-272, a G9a/DNMT inhibitor, inhibited cell proliferation in some bladder cancer cell lines, and cell lines resistant to CM-272 had mutations in PIK3CA. Because G9a and EZH2 coregulate H3K27me3 and activating mutations in PIK3CA reduce EZH2 and H3K27me3 in bladder cancer, CM-272 resistance may be related to EZH2 activity; supporting this, PIK3CA-mutant bladder cancer cells had decreased EZH2 levels, and PIK3CA-mutant bladder cancer cells exhibited EZH2 downregulation, reduced H3K27me3, and CM-272 resistance. Further, expression of transcripts bound by both G9a and EZH2 distinguished recurrent from nonrecurrent bladder cancer. In a mouse model of bladder cancer, primary tumors and metastases had increased G9a, EZH2, H3K27me2, and H3K27me3 levels and exhibited ribosomal protein S6, PKB/AKT, ERK, and STAT3 activation. Treating these mice with CM-272 or with CM-272 with cisplatin produced superior reductions in primary and metastatic tumor burden compared with controls and those in the cisplatin-only group; most mice in the dual-treatment group had only remnants of tumors. CM-272 led to upregulation of genes involved in modulating immune responses in bladder cancer cell lines, and combination with anti–PD-L1 heightened the immune response against primary and metastatic tumors in the mice and produced a sustained reduction in or elimination of tumor burden. In patients with bladder cancer who did not respond to anti–PD-1, expression of G9a and EZH2 was increased, as were H3K27me2 and H3K27me3. Collectively, these results support exploration of CM-272 as a bladder cancer therapy and provide potential biomarkers for immunotherapy response.

Segovia C, San José-Enériz E, Munera-Maravilla E, Martínez-Fernández M, Garate L, Miranda E, et al. Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nat Med 2019;25:1073–81.

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