Coleman, R. | Search bioRxiv

bioRxiv2018

EZH2 co-opts gain-of-function p53 mutants to promote cancer growth and metastasis

With the unfolding of more and more cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target different mutants rather than develop strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation sequencing (RIP-seq) we identified EZH2 as a p53 mRNA-binding protein. EZH2 bound to the internal ribosome entry site (IRES) in the 5 untranslated region (5UTR) of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner. EZH2 augmented p53 GOF mutant-mediated cancer growth and metastasis by increasing p53 GOF mutant protein level. EZH2 overexpression associated with the worse outcome only in patients with p53-mutated cancer. Depletion of EZH2 by antisense oligonucleotides inhibited p53 GOF mutant-mediated cancer growth. Our findings reveal a non-methyltransferase function of EZH2 that controls protein translation of p53 GOF mutants, inhibition of which causes synthetic lethality in cancer cells expressing p53 GOF mutants.

cancer biology↗

bioRxiv2017

Hox-logic of preadaptations for social insect symbiosis in rove beetles

How symbiotic lifestyles evolve from free-living ecologies is poorly understood. In Metazoas largest family, Staphylinidae (rove beetles), numerous lineages have evolved obligate behavioral symbioses with ants or termites. Widespread convergence of this lifestyle is thought to stem from a novel, chemically defended body plan that enables free-living species to infiltrate colonies and undergo extreme evolutionary specialization. Here we show how this innovative body plan evolved, via new Hox functions in staphylinids that remodeled the coleopteran groundplan. Using a model staphylinid, Dalotia coriaria, we reveal the Hox basis for changes in thoracic appendage morphology that shortened the beetle elytron and left the abdomen physically unprotected, selecting for an abdominal defense gland that was likely key to unlocking ant and termite societies. We present evidence that the gland evolved through a novel, combinatorial role of the abdominal Hox proteins AbdA and AbdB. These proteins function together to specify distinct gland cell types in neighboring segmental compartments, each cell type synthesizing a different class of compound--irritant, ester and solvent. Only when secreted together do these compounds constitute a bioactive secretion, providing an example of emergent chemical functionality that arises from synergy between individual gland cell types. Hox-controlled specification of glandular diversity implies a modularity in compound biosynthesis that likely catalyzed the evolvability of rove beetle chemistry, including the capacity of symbiotic taxa to produce potent compounds for host deception. This study reveals how Hox-controlled body axis modifications predispose a major animal to convergently evolve into symbionts.

evolutionary biology↗