Lysine acetyltransferase 5 in EGFR mutated non-small cell lung cancer

Histone modifications are crucial in activities such as transcriptional activation, gene silencing, and epigenetic cellular memory. In particular, lysine acetylation via lysine (K) acetyltransferases (KATs) has been implicated in cancer development. Interestingly, KAT5, also known as Tip60 (tat-interactive protein-60kDa), has been reported to possess both tumor promoting and tumor suppressing properties depending on the context of malignancy. Herein we report that KAT5 contributes to tumorigenesis in epidermal growth factor receptor (EGFR) mutated lung cancer, and Kat5-knockout mice models demonstrate significantly reduced lung tumor burden. To probe the aberrant modification of KAT5, we demonstrated that KAT5 binds to and is phosphorylated by oncogenic EGFR in co-immunoprecipitation experiments. Next, to investigate whether KAT5 is involved in cell proliferation and survival, H1975 cells harboring L858R-T790M double-activating mutations were transfected with doxycycline inducible short helical RNA (shRNA) targeting KAT5 (shKAT5). Following treatment, shKAT5 cells were observed to have suppressed proliferation rates. Pharmacological inhibition using TH1834, a known KAT5 inhibitor, also suppressed proliferation rates in shKAT5 cells; in contrast BEAS2B cells, an immortalized normal human bronchial cell line, surprisingly exhibited increased viability compared to transformed human lung H1975 cells. This finding supports KAT5’s context-dependent role in in normal and abnormal cell homeostasis. To further investigate KAT5 in lung tumorigenesis in vivo, we generated EGFR-mutant conditional Kat5 knockout mice using a tetracycline-induced Cre/loxP system. Following doxycycline treatment for 10 weeks, isolated mice lungs for EGFRTL/CCSP-rtTA/Cre/Kat5F/F possessed significantly lower tumor volume compared to EGFRTL/CCSP-rtTA/Cre/Kat5wt/F and EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt mice lungs. Hemotoxylin and eosin staining showed no evident hyperproliferation in lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5F/F mice whereas lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt and EGFRTL/CCSP-rtTA/Cre/Kat5wt/F did, signifying that KAT5 has a potential regulatory role in cellular proliferation. RNA-Seq analysis of shKAT5 H1975 cells identified downstream targets involved in tumorigenic pathways. Subsequent quantitative polymerase chain reaction (PCR) of shKAT5 cells served to validate the reported targets. Taken together, these data offer insight into a KAT5 mediated oncogenic pathway that can provide novel therapeutic approaches in treating lung cancer

Propagation of Delayed Lattice Differential Equations without Local Quasimonotonicity

This paper is concerned with the traveling wave solutions and asymptotic spreading of delayed lattice differential equations without quasimonotonicity. The spreading speed is obtained by constructing auxiliary equations and using the theory of lattice differential equations without time delay. The minimal wave speed of invasion traveling wave solutions is established by presenting the existence and nonexistence of traveling wave solutions

Information Flow Model for Commercial Security

Information flow in Discretionary Access Control (DAC) is a well-known difficult problem. This paper formalizes the fundamental concepts and establishes a theory of information flow security. A DAC system is information flow secure (IFS), if any data never flows into the hands of owner’s enemies (explicitly denial access list.

The Influence of Body Size and Hemoglobin Multiplicity on Critical Oxygen Threshold in Red Drum (Sciaenops ocellatus)

Hypoxia is common in marine environments and fishes use a suite of cardiorespiratory adjustments to defend aerobic metabolism, including reducing standard metabolic rate (SMR), the minimum metabolic rate needed to sustain life at a specified temperature, or increasing hemoglobin (Hb)-O2 affinity. Nonetheless, hypoxia can constrain oxygen transport whereby fish cannot accommodate standard metabolic rate; a point known as critical oxygen tension (Pcrit). Currently, it is unclear how life history traits may impact Pcrit, but available data on red drum (Sciaenops ocellatus) suggest that its SMR decreases with size, and its transcriptome contains multiple Hb-α and Hb-β subunits. Therefore we sought to explore the influence of body size and acclimation to hypoxia. Critical oxygen tension (Pcrit) was measured for fish over a 2500-fold range in mass (0.26 - 686 g) and surprisingly showed an increase (Pcrit = 3.15 logM + 16.19; R2 = 0.44) despite decreasing SMR. Two groups of S. ocellatus (90.96 ± 5.00 g ranging from 69.7 g to 141.9 g) were also subjected to either normoxia ( > 95% P_(O_2 )) or hypoxia (30%±5% P_(O_2 )) treatment for two weeks. Only fish subjected to hypoxia treatment showed a statistically significant decrease in Pcrit after the treatment. Acclimation had no impact on gill surface area, diffusion distance or relative ventricular mass, but mRNA expression levels of the major Hb-α subunit switched from Hbα-3.1 in the normoxia group to Hbα-3.2 in the hypoxia treatment group and expression levels of Hbα-2, Hbα-3.2 and Hbβ-3.1 showed a statistically significant increase in the hypoxia treatment group. Decrease in P50 and thus an increase in Hb-O2 binding affinity was observed for fish subjected to hypoxia treatment. Taken together these data indicate that hypoxia tolerance is affected by both developmental stage and hypoxia acclimation.Integrative Biolog