SUMMARY Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here, we show through lineage tracing and genetic ablation that BMI1+ CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, quiescent, and cisplatin-resistant BMI1+ CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy and eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis.

These findings suggest a potentially important role for extravasated, modified LDL in promoting DR by promoting apoptotic pericyte loss.

Rapid and robust induction of type I IFN (IFN-I) is a critical event in host antiviral innate immune response. It has been well demonstrated that cyclic GMP-AMP (cGAMP) synthase (cGAS) plays an important role in sensing cytosolic DNA and triggering STING dependent signaling to induce IFN-I. However, it is largely unknown how cGAS itself is regulated during pathogen infection and IFN-I production. In this study, we show that pattern recognition receptor (PRR) ligands, including lipid A, LPS, poly(I:C), poly(dA:dT), and cGAMP, induce cGAS expression in an IFN-I–dependent manner in both mouse and human macrophages. Further experiments indicated that cGAS is an IFN-stimulated gene (ISG), and two adjacent IFN-sensitive response elements (ISREs) in the promoter region of cGAS mediate the induction of cGAS by IFN-I. Additionally, we show that optimal production of IFN-β triggered by poly (dA:dT) or HSV-1 requires IFNAR signaling. Knockdown of the constitutively expressed DNA sensor DDX41 attenuates poly(dA:dT)-triggered IFN-β production and cGAS induction. By analyzing the dynamic expression of poly(dA:dT)-induced IFN-β and cGAS transcripts, we have found that induction of IFN-β is earlier than cGAS. Furthermore, we have provided evidence that induction of cGAS by IFN-I meditates the subsequent positive feedback regulation of DNA-triggered IFN-I production. Thus, our study not only provides a novel mechanism of modulating cGAS expression, but also adds another layer of regulation in DNA-triggered IFN-I production by induction of cGAS.

SUMMARY Histone modifications play important roles in regulating DNA-based biological processes. Of the modified sites, histone H3 lysine 56 (H3K56) is unique in that it lies within the globular core domain near the entry-exit sites of the nucleosomal DNA superhelix and its acetylation state in yeast is a marker for newly synthesized histones in transcription, DNA repair and DNA replication. We now report the presence of H3K56 monomethylation (H3K56me1) in mammalian cells and find that the histone lysine methytransferase G9a/KMT1C is required for H3K56me1 both in vivo and in vitro. We also find that disruption of G9a or H3K56 impairs DNA replication. Furthermore, H3K56me1 associates with the replication processivity factor PCNA primarily in G1 phase of the cell cycle and directly, in vitro. These results find H3K56me1 in mammals and indicate a role for H3K56me1 as a chromatin docking site for PCNA prior to its function in DNA replication.