Morancho, B. | Search bioRxiv

bioRxiv2020

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells.

cancer biology↗

bioRxiv2017

DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

Recent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

cancer biology↗