Summary Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with dissemination of the ‘bad luck’ hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (<10~30%) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. Next, we show that intrinsic risk is better estimated by the lower bound risk controlling for total stem cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results carry immense consequences for strategizing cancer prevention, research, and public health.

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA

Summary c-Myc is known to promotes glutamine usage by up-regulating glutaminase (GLS), which converts glutamine to glutamate that is catabolized in the TCA cycle. Here we report that in a number of human and murine cells and cancers, Myc induces elevated expression of glutamate-ammonia ligase (GLUL), also termed glutamine synthetase (GS), which catalyzes the de novo synthesis of glutamine from glutamate and ammonia. This is through upregulation of a Myc transcriptional target thymine DNA glycosylase (TDG), which promotes active demethylation of the GS promoter and its increased expression. Elevated expression of GS promotes cell survival under glutamine limitation, while silencing of GS decreases cell proliferation and xenograft tumor growth. Upon GS overexpression, increased glutamine enhances nucleotide synthesis and amino acid transport. These results demonstrate an unexpected role of Myc in inducing glutamine synthesis, and suggest a novel molecular connection between DNA demethylation and glutamine metabolism in Myc-driven cancers.

Discriminating the contribution of unmodifiable random intrinsic DNA replication errors (‘bad luck’) to cancer development from those of other factors is critical for understanding cancer in humans and for directing public resources aimed at reducing the burden of cancer. Here, we review and highlight the evidence that demonstrates cancer causation is multifactorial, and provide several important examples where modification of risk factors has achieved cancer prevention. Furthermore, we stress the need and opportunities to advance understanding of cancer aetiology through integration of interaction effects between risk factors when estimating the contribution of individual and joint factors to cancer burden in a population. We posit that non-intrinsic factors drive most cancer risk, and stress the need for cancer prevention.

It remains uncertain how the DNA sequence of mammalian genes influences the transcriptional response to extracellular signals. Here, we show that the number of CREB-binding sites (CREs) affects whether the related histone acetyltransferases (HATs) CREB-binding protein (CBP) and p300 are required for endogenous gene transcription. Fibroblasts with both CBP and p300 knocked-out had strongly attenuated histone H4 acetylation at CREBtarget genes in response to cyclic-AMP, yet transcription was not uniformly inhibited. Interestingly, dependence on CBP/p300 was often different between reporter plasmids and endogenous genes. Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non-HAT coactivator of CREB). Indeed, CRTC2 rescued cAMP-inducible expression for certain genes in CBP/p300 null cells and contributed to the CBP/p300-independent expression of other targets. Thus, endogenous genes with a greater local concentration and diversity of coactivators tend to have more resilient-inducible expression. This model suggests how gene expression patterns could be tuned by altering coactivator availability rather than by changing signal input or transcription factor levels.

The effect of fish meal (FM) substitution with fermented soybean meal (FSBM) in the diets of the carnivorous marine fish, black sea bream, Acanthopagrus schlegelii, was investigated. An 8-wk feeding trial was conducted with black sea bream (11.82 ± 0.32 g; mean initial weight) in indoor flowthrough fiberglass tanks (25 fish per tank). Six isonitrogenous and isoenergetic diets were formulated, in which FM was replaced by FSBM at 0% (control diet), 10% (FSBM10), 20% (FSBM20), 30% (FSBM30), 40% (FSBM40), or 50% (FSBM50), respectively. Each diet was fed to triplicate groups of fish twice daily to apparent satiation. The results showed that there was no difference in survival of black sea bream during the feeding trial. Fish fed the FSBM10 or FSBM20 diet showed comparable growth performance compared with fish fed the control diet (P > 0.05), whereas more than 30% replacement of FM adversely affected weight gain and specific growth rate (P < 0.05). Feed intake was significantly lower for fish fed the FSBM50 diet compared with fish fed the control diet. Feed conversion ratio (FCR) tended to increase with increasing dietary FSBM with the poorest FCR observed for fish fed the FSBM50 diet. Protein efficiency ratio and protein productive values showed similar patterns. Apparent digestibility of nutrients significantly decreased with increasing dietary FSBM level. With the exception of protein content, no significant differences in whole body and dorsal muscle composition were observed in fish fed the various diets. Fish fed the FSBM50 diet had significantly lower intraperitoneal ratio than fish fed the control or FSBM10 diet. Hepatosomatic index and condition factor were unaffected by dietary treatments. This study showed that up to 20% of dietary FM protein could be replaced by FSBM protein in the diets of juvenile black sea bream.

Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-β signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreased cell invasion and proliferation, and increasing cell cycle arrest. Ectopic expression of hsa-miR-140-5p in colorectal CSCs inhibited CSC growth and sphere formation in vitro by disrupting autophagy. We have systematically identified targets of hsa-miR-140-5p involved in autophagy. Furthermore, overexpression of hsa-miR-140-5p in CSCs abolished tumor formation and metastasis in vivo. In addition, there is a progressive loss of hsa-miR-140-5p expression from normal colorectal mucosa to primary tumor tissues, with further reduction in liver metastatic tissues. Higher hsa-miR-140 expression is significantly correlated with better survival in stage III and IV colorectal cancer patients. The functional and clinical significance of hsa-miR-140-5p suggests that it is a key regulator in CRC progression and metastasis, and may have potential as a novel therapeutic molecule to treat CRC.

SUMMARY Gene expression burdens cells by consuming resources and energy. While numerous studies have investigated regulation of expression level, little is known about gene design elements that govern expression costs. Here, we ask how cells minimize production costs while maintaining a given protein expression level and whether there are gene architectures that optimize this process. We measured fitness of ~14,000 E. coli strains, each expressing a reporter gene with a unique 5′ architecture. By comparing cost-effective and ineffective architectures, we found that cost per protein molecule could be minimized by lowering transcription levels, regulating translation speeds, and utilizing amino acids that are cheap to synthesize and that are less hydrophobic. We then examined natural E. coli genes and found that highly expressed genes have evolved more forcefully to minimize costs associated with their expression. Our study thus elucidates gene design elements that improve the economy of protein expression in natural and heterologous systems.