Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption [chronic jetlag (CJL)] increases tumor burden in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.

Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.

In many applications, it is desirable for photocured adhesives to have high‐mechanical strength in the cured state, but relatively low viscosity when liquid. This was achieved by adding less than 0.5 wt% hydroxyapatite and graphene to methyl methacrylate with diurethane dimethacrylate (UDMA‐MMA). Nanoindentation shows hardness increasing by 30–40% and indentation modulus by >30% compared to UDMA‐MMA on its own. Rheometry shows only a small increase in uncured viscosity for the liquid state. The additives affect the optical properties, mobility of free radicals, photocuring, and degree of conversion, the effects of which are seen in Fourier transform infrared and micro‐Raman spectra. Thermographic images taken during curing show that the additives impact the photocuring process. In addition, changes in intermolecular bonding are seen in the vibrational spectra when the additives are present. The enhanced mechanical properties are attributed to the observed changes in photocuring and bonding.

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The zinc finger protein Zc3h8 is overexpressed in many mouse and human solid tumors. We have shown that increased expression of Zc3h8 in cultured mouse mammary cells is associated with increased proliferation rate, increased motility and invasiveness, increased capacity for growth in three dimensions, and increased capacity for tumor formation. Partial knockdown of Zc3h8 expression from mouse mammary tumor cells has the opposite effect. The Zc3h8 protein localizes to both PML bodies and Cajal bodies in the nucleus and features of this localization are altered by treatment of cells with a casein kinase 2 inhibitor, TBB. We have embarked upon an analysis of the contributions of structural features of the Zc3h8 protein through mutagenesis of the gene at key positions. The casein kinase 2 phosphorylation site at position T32 was mutated to either an alanine to prevent phosphorylation, or to glutamic acid to mimic constitutive phosphorylation. Each of the three zinc fingers in the C-terminal region was mutated to replace one cysteine residue. The mutations were introduced into a variant of the zc3h8 gene that has 6 mutations introduced at synonymous positions in order to escape knockdown by RNAi, although the protein sequence generated is identical to the original Zc3h8. Each of the mutant constructs was introduced into mouse mammary tumor cells with knockdown of the endogenous Zc3h8. Mutation of the phosphorylation site T32A led to the formation of fewer, although larger PML bodies, with continued ZC3h8 co-localization. The T32E mutant, with constitutive negative charge at this position led to the formation of a large number of small nuclear foci. Mutant constructs were stably transfected into tumor cells with knockdown of endogenous Zc3h8, and behavior of the mutants was compared to the behavior of cells transfected with the synonymously mutated gene construct. Disruption of each of the zinc fingers individually led to decreased proliferation rate, decreased growth as spheroids or in soft agar, and decreased invasion through Matrigel relative to the synonymous Zc3h8. Tumor cells with Zc3h8 knockdown failed to form tumors in syngeneic BALB/c mice within 10 weeks, while cells transfected with a negative control vector formed tumors in all animals. Rescue of Zc3h8 expression with the synonymous mutant led to tumor formation in 50% of the animals, while no tumors formed from cells transfected with zinc finger mutants. We conclude that the zinc fingers contribute to aggressive tumor cell behavior while the T32 phosphorylation site is essential for proper localization to nuclear bodies. Citation Format: John A. Schmidt, Emily R. Duffner, Emily M. Harris, Tyler Doan, Emanuel Irizarry, Keith G. Danielson, Janice E. Knepper. Structural analysis of features contributing to the oncogenic phenotype conferred by the zinc finger nuclear body protein Zc3h8 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2484.