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Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis.

ABSTRACT: Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat's antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.

SUBMITTER: Morales Torres C

PROVIDER: S-EPMC7156485 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis.

Morales Torres Cristina C Wu Mary Y MY Hobor Sebastijan S Wainwright Elanor N EN Martin Matthew J MJ Patel Harshil H Grey William W Grönroos Eva E Howell Steven S Carvalho Joana J Snijders Ambrosius P AP Bustin Michael M Bonnet Dominique D Smith Paul D PD Swanton Charles C Howell Michael M Scaffidi Paola P

Nature communications 20200414 1

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-toler ...[more]

PMID: 32286289

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Project description:Background Glioma-initiating cells (GICs) are the source of glioma cells that can self-renew, have pluripotency, and are treatment-resistant, so are the starting point for relapse and eventual death despite multimodality therapy. L-[methyl-11C] methionine PET has observed high accumulation at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. Methods We cultured cells in methionine-deprived culture medium for comprehensive analysis. Based on the obtained results, the possible target molecules were chemically inhibited and the respective markers were analyzed. Results Methionine depletion markedly decreased proliferation and increased cell death of GICs. Decreased S-adenosyl-methionine, which is synthesized intracellularly by catalyzed by methionine adenosyltransferase using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotency of stem cells, (iii) decreased expression of the core-genes and pluripotent markers of stem cells including FOXM1, SOX2, SOX4, PROM1, and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2, and (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, small nucleolar RNA guiding the pseudouridylation of 28S rRNA, which is essential for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine depletion and decreases in stem cell markers and small nucleolar RNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project database and compared between tumor cells with relatively low methionine levels in areas of pseudopalisading arrangement around necrosis and tumor cells in the infiltrating region, showing that cells in the infiltrating region have higher capacity to produce cholesterol. Conclusions Methionine metabolism is closely related with self-renewal, pluripotency, and cell death in GICs through modification of cholesterol biosynthesis, especially in the SREBF2-FOXM1 and ACA43 axis with modification of rRNA. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10280-5.

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Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis.

Publications

Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis.

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