Identification of a novel minor-groove DNA binder that represses mitochondrial genes expression and induces apoptosis in highly aggressive leiomyosarcoma cells
The induction of cellular stress is a common strategy in cancer therapy. Leiomyosarcomas (LMS) are aggressive tumors for which there are few effective therapeutic options. Through a combination of in silico and in vitro screens, the compound NSC-260594/XMH95 was identified as a promising molecule that selectively induces apoptosis in aggressive LMS cells. This apoptotic response is associated with the upregulation of the BH3-only genes PMAP1/NOXA, BIK, HRK and BBC3/PUMA. XMH95 binds DNA and possibly the minor groove, similar to Hoechst 33258. Unlike Hoechst, XMH95 is not fluorescent but can be photoactivated by UV irradiation when bound to DNA. Also, unlike Hoechst, XMH95 suppresses mitochondrial gene expression and is a more effective inducer of apoptosis. Apart from suppressing mitochondrial genes, XMH95 has many effects on gene expression that are common to Hoechst. Using an inhibitor of mitochondrial RNA polymerase (POLRMT), we show that XMH95 triggers apoptosis by perturbing both nuclear and mitochondrial transcription. Our results propose a new compound and a novel stress that can trigger apoptosis in aggressive cancer cells by upregulating multiple BH3-only genes. Overall design: RNA-seq profiling of HUtSMC and SK-UT-1 cells treated with by two double strand DNA binders: Hoechst 33 and NSC26954/XMH95.