Silver, A. | bioRxiv Science

bioRxiv2020

NOVEL NUCLEAR ROLE OF HDAC6 IN PROGNOSIS AND THERAPEUTIC TARGET FOR COLORECTAL CANCER

Histone deacetylase 6 (HDAC6) inhibition is a potential treatment of a wide range of cancer types via the acetylation of diverse proteins in the cytoplasm. However, the regulation of histone acetylation and the maintenance of higher-order chromatin structure remains unidentified. Here, we investigated the effect of selective inhibition of HDAC6 by histone acetylation, chromatin relaxation assays, co-immunoprecipitation, acetylome peptide array and in vivo RNA microarray. Our data shows that nuclear HDAC6 physically interacts with the Histone 4 lysine 12 residue, and that HDAC6 inhibition increases acetylation specifically at this residue in several cancer types. Inhibition induces major chromatin structure modulation, but has no equivalent effect on knockout HDAC6-/- MEF cells. We identified several novel HDAC6-deacetylated substrates and high expression of HDAC6 in colorectal cancer (CRC) tissue association with reduced levels of H4K12ac and independent of the key CRC driver mutations, but positively associated with EGFR expression. Furthermore, in vivo HDAC6 inhibition induces significant tumor regression in a CRC xenograft mice model with significant changes in the expression of functional nuclear genes. We also demonstrated that a DNA damaging agent in combination with selective HDAC6 inhibition is effective and acts synergistically, inducing chromatin relaxation and increased cell death in CRC cells. CRC tissues (Normal versus tumor; n=58 matched pairs) together with TCGA data analysis of 467 CRC patients showed that high HDAC6 expression is associated with metastasis, overall and disease-free survival, and is an independent risk factor of CRC stage progression. Our findings designate a new role for nuclear HDAC6 both in cancer prognosis and as a new therapeutic target for CRC and other types of cancer. HighlightHistone deacetylases 6 activity; Chromatin relaxation; Histone modifications; Gene array; DOX: doxorubicin; OXA: oxaliplatin; 5-FU: fluorouracil; Ac: acetylation; MNase: Micrococal nuclease.

cancer biology↗

bioRxiv2020

Persistence of the ground beetle (Coleoptera: Carabidae) microbiome to diet manipulation

Host-associated microbiomes can play important roles in the ecology and evolution of their insect hosts, but bacterial diversity in many insect groups remains poorly understood. Here we examine the relationship between host environment, host traits, and microbial diversity in three species in the ground beetle family (Coleoptera: Carabidae), a group of roughly 40,000 species that synthesize a wide diversity of defensive compounds. This study found that the ground beetle microbiome is consistent across different host food sources. We used 16S amplicon sequencing to profile three species that are phylogenetically distantly related, trophically distinct, and whose defensive chemical secretions differ: Anisodactylus similis LeConte, 1851, Pterostichus serripes (LeConte, 1875), and Brachinus elongatulus Chaudoir, 1876. Wild-caught beetles were compared to individuals maintained in the lab for two weeks on carnivorous, herbivorous, or starvation diets. Soil environment but not diet had a significant effect on bacterial diversity and composition. The three carabid species have patterns of microbial diversity similar to those previously found in other insect hosts. Metagenomic samples from two highly active tissue types -- guts, and pygidial gland secretory cells (which produce defensive compounds) -- were processed and sequenced separately from those of the remaining body. The observed similarity of the pygidial gland secretory cell microbiome across hosts suggests the possibility that it may be a conserved community, possibly due to functional interactions related to defensive chemistry. These results provide a baseline for future studies of the role of microbes in the diversification of defensive chemical biosynthesis in carabids.

ecology↗