The mechanism by which the eukaryotic DNA-replication machinery penetrates condensed chromatin structures to replicate the underlying DNA is poorly understood. Here we provide evidence that an ACF1-ISWI chromatin-remodeling complex is required for replication through heterochromatin in mammalian cells. ACF1 (ATP-utilizing chromatin assembly and remodeling factor 1) and an ISWI isoform, SNF2H (sucrose nonfermenting-2 homolog), become specifically enriched in replicating pericentromeric heterochromatin. RNAi-mediated depletion of ACF1 specifically impairs the replication of pericentromeric heterochromatin. Accordingly, depletion of ACF1 causes a delay in cell-cycle progression through the late stages of S phase. In vivo depletion of SNF2H slows the progression of DNA replication throughout S phase, indicating a functional overlap with ACF1. Decondensing the heterochromatin with 5-aza-2-deoxycytidine reverses the effects of ACF1 and SNF2H depletion. Expression of an ACF1 mutant that cannot interact with SNF2H also interferes with replication of condensed chromatin. Our data suggest that an ACF1-SNF2H complex is part of a dedicated mechanism that enables DNA replication through highly condensed regions of chromatin.

Nuclear accumulation of β-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of β-catenin in response to Wnt signaling. Glucose-dependent β-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger β-catenin acetylation. Consequently β-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/β-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.

Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITF High melanoma cell proliferation. By contrast MITF Low cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.

Increasing evidence suggests a complex relationship between obesity, diabetes and cancer. Here we review the evidence for the association between obesity and diabetes and a wide range of cancer types. In many cases the evidence for a positive association is strong, but for other cancer types a more complex picture emerges with some site-specific cancers associated with obesity but not to diabetes, and some associated with type I but not type II diabetes. The evidence therefore suggests the existence of cumulative common and differential mechanisms influencing the relationship between these diseases. Importantly, we highlight the influence of antidiabetics on cancer and antineoplastic agents on diabetes and in particular that antineoplastic targeting of insulin/IGF-1 signalling induces hyperglycaemia that often evolves to overt diabetes. Overall, a coincidence of diabetes and cancer worsens outcome and increases mortality. Future epidemiology should consider dose and time of exposure to both disease and treatment, and should classify cancers by their molecular signatures. Well-controlled studies on the development of diabetes upon cancer treatment are necessary and should identify the underlying mechanisms responsible for these reciprocal interactions. Given the global epidemic of diabetes, preventing both cancer occurrence in diabetics and the onset of diabetes in cancer patients will translate into a substantial socioeconomic benefit.

Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes-cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/b-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to b-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on b-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers.