Highlights d Serum starvation recruits TFIIIC at ADNP-bound Alu Elements (AEs) near Pol II genes d TFIIIC-associated histone acetylase activity acetylates H3K18 over the bound AEs d TFIIIC-bound acetylated AEs loop to contact CTCF at distal cell-cycle genes' promoters d CTCF-TFIIIC interaction ensures rapid cell-cycle genes' reactivation on serum exposure

The mammalian genome is shaped by the expansion of repetitive elements and its folding is governed by epigenetic modifications and architectural proteins. However, the precise way all these factors interact to coordinate genome structure and expression is poorly understood. Here we report that upon serum starvation TFIIIC, a general transcription factor, binds a subset of Alu elements close to cell cycle genes and rewires genome topology via direct histone acetylation and promoter-anchored chromatin loops to distant genes. These changes ensure basal transcription of crucial cell cycle genes and their re-activation upon serum re-exposure. Our study unveils a novel function of TFIIIC on gene expression and genome folding achieved through casting direct manipulation of the epigenetic state of Alu elements to adjust 3D genome function.

In this model, the emergence of radiation resistance was associated with the acquisition of biological traits that support more aggressive behaviour of cancer cells. We have generated a model that will be useful for mechanistic studies and development of rational treatments against radiation resistance in cancer.

Radiotherapy (XRT) delivered with the antibody cetuximab is a standard treatment option for squamous cell carcinomas of head and neck (SCCNH). Cetuximab acts by blocking epidermal growth factor receptor (EGFR) signaling to inhibit cancer progression. However, a significant percentage of patients will not respond to XRT and cetuximab. Statins reduce the synthesis of cholesterol and isoprenoid derivates that may be required for efficient EGFR signaling. We assessed whether the statin simvastatin could improve this combined therapy. In vitro, simvastatin enhanced the effects of XRT alone and in combination with cetuximab in wound healing, cell proliferation, and clonogenic assays in FaDu cells. These results were reflected in xenoimplanted tumors growing into subcutaneous tissue of athymic mice where concomitant treatment with simvastatin decreased tumor growth. Consistently, lower levels of phosphorylated extracellular signal–regulated kinases 1 and 2, phosphatidylinositol 3-kinase/AKT–protein kinase B, and signal transducer and activator of transcription 3 oncoproteins and higher levels of caspase-3 and apoptosis in cell cultures and xenografts were observed. The EGFR-overexpressing A431 cell line was used to reproduce these antitumor effects of simvastatin. Our findings suggest that simvastatin may improve the efficiency of concomitant XRT and cetuximab. Further investigation in the treatment of SCCNH is warranted.