Transcriptional control in inflammation and cancer

Research project

A large body of epidemiological and experimental data demonstrated a direct link between chronic inflammation and the development of several types of epithelial cancers worldwide, including hepatocarcinomas, colon carcinomas, gastric and prostate cancer. Moreover, most cancers contain an inflammatory infiltrate that is hijacked by tumor cells to promote angiogenesis, tissue invasion and cell proliferation. In vivo experiments in mouse models have demonstrated that modulation of tumor properties by inflammatory cells requires the transcription factors of the NF-kB/Rel family, thus suggesting the possible use of anti-NF-kB drugs in tumor therapy.

Research activity in the laboratory is focused on understanding the molecular control of inflammatory gene expression and the epigenetic mechanisms linking chronic inflammation to cancer development.

The NF-kB family of transcription factors
In mammals most cell types contain a collection of NF-kB dimers composed by homo- and hetero-typic combinations of the five transcription factors of the mammalian NF-kB/Rel family: p65/RelA, c-Rel, RelB, p50 and p52. These proteins contain a highly homologous Rel Homology Region (RHR) that mediates protein-DNA interactions and dimerization, as well as interactions with inhibitory proteins known as IkBs. Depending on the cell type and the differentiation status, the relative abundance of each dimer may vary, thus generating a high degree of complexity. The main regulatory switch in the NF-kB system is cytoplasmic and consists in the release of NF-kB from the IkBs. This activation step is mediated by the recently discovered IkB kinase (IKK), which phosphorylates amino-terminal regulatory serines in the IkBs and targets them for proteasomal degradation, thus liberating the NF-kBs and allowing them to enter the nucleus. However, it is becoming increasingly clear that in addition to this required activation step, both NF-kB recruitment to target genes and post-recruitment NF-kB-induced transcriptional events are actively regulated. All NF-kB dimers share the ability to bind a family of 9-11 nt DNA-binding sites collectively known as kB sites and conventionally represented as G_-5G_-4G_-3R_-2N_-1N0Y₊₁Y₊₂C₊₃C₊₄ (R=purine, N= any nucleotide, Y= pyrimidine). In spite of similar DNA-binding profiles, NF-kB dimers are not equivalent in terms of transcriptional activation properties since each one of them activates specific subsets of genes and has different potency at genes that are activated in a redundant fashion.

Biological functions of NF-kB: the cancer connection
Understanding principles underlying transcriptional regulation by NF-kB proteins is an important scientific task with potential biomedical implications. NF-kB is an essential regulator of several essential biological responses. First, it is required for the induction of the innate and adaptive immune response, regulating critical functions in essentially every cell type of the immune system. Second, it is both directly and indirectly connected to cancer development. Indirect connections arise from its essential role in the regulation of inflammation. NF-kB activation in non-transformed cells of the tumor stroma, like fibroblasts, endothelial cells and macrophages contributes to tumor initiation and progression by mediating transcriptional induction of soluble mediators that amplify angiogenesis and neoplastic cell proliferation, and also affect progression to more advanced tumor stages. Direct connections depend on the role of NF-kB as a switch in survival decisions in cancer cells: transcriptional activation of anti-apoptotic genes mediates such effects and modulates not only survival of the tumor but also its responsiveness to therapy.

An outline of the research in the lab
The first objective of the lab is the mechanistic understanding of transcriptional regulation of inflammatory genes both in inflammatory cells (like macrophages) and in bystander cells exposed to an inflammatory environment. An in-depth understanding of such mechanisms may provide the molecular basis for therapeutic targeting of subsets of NF-kB-regulated transcriptional events (such as small-molecule-based drugs interfering with NF-kB interaction with transcriptional coregulators). To achieve these objectives, standard biochemical approaches to transcription are integrated with bioinformatics, imaging and in vivo studies. The second main research area relates to the epigenetic mechanisms that link chronic inflammation to cancer initiation and progression. We are analyzing how inflammatory stimuli modify activity or expression of epigenetic modifiers (including enzymes directly acting on chromatin) and how such changes impact on maintenance of genomic stability.