The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses. We have found that LSD1 is recruited to demethylate IFITM3 at position K88 under IFNα treatment. However, infection by either Vesicular Stomatitis Virus (VSV) or Influenza A Virus (IAV) triggers methylation of IFITM3 by promoting its disassociation from LSD1. Accordingly, inhibition of the enzymatic activity of LSD1 by Trans-2-phenylcyclopropylamine hydrochloride (TCP) increases IFITM3 monomethylation which leads to more severe disease outcomes in IAV-infected mice. In summary, our findings highlight the opposite role of LSD1 in fighting RNA viruses comparing to DNA viruses infection. Our data suggest that the demethylation of IFITM3 by LSD1 is beneficial for the host to fight against RNA virus infection.

Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. The effects of CAFs on the progression of colorectal cancer (CRC) remain controversial. In this study, we found the ectopic overexpression of Fibronectin leucine-rich transmembrane protein 3 (FLRT3) inhibited the process of Epithelial-mesenchymal transition (EMT), as well as the proliferation, migration, invasion, and promote apoptosis of CRC cells, whereas silencing FLRT3 expression resulted in the opposite phenomenon. FLRT3 downregulation was associated with a poor prognosis in CRC. Also, FLRT3 expression was significantly related to some clinicopathological factors, including T stage (p=0.037), N stage (p=0.042), and E-cadherin (p=0.002) level. Via univariate and multivariate analyses, M stage (p<0.0001), FLRT3 (p=0.044), and E-cadherin (p=0.003) were associated with overall survival and were independent prognostic factors for it. Mechanistically, CAFs secreted TGF-β, which downregulated FLRT3 expression by activating SMAD4 to promote aggressive phenotypes in CRC cells. Moreover, FLRT3 repressed tumorigenesis and lung metastasis, which could be reversed by LY2109761, a dual inhibitor of TGF-β receptor type I and II. Treatment with LY2109761 increased IFN-γ expression in CD8+ T cells and reduced the number of regulatory T cells in the tumor microenvironment. Taken together, we revealed the metastasis-suppressive function of FLRT3, which was attenuated during the CAFs-mediated activation of the TGF-β/SMAD4 signaling pathway to promote EMT in CRC. LY2109761 that significantly inhibited metastasis could be a new treatment option for advanced CRC. Implications: CAFs enhance CRC aggressiveness by reducing FLRT3 expression through activating TGF-β/SMAD4 signaling pathway. CAFs-targeted therapy and/or LY2109761 were promising treatments for CRC.

Supplementary Table from TGF-β-Induced FLRT3 Attenuation Is Essential for Cancer-Associated Fibroblast–Mediated Epithelial–Mesenchymal Transition in Colorectal Cancer

Supplementary Figure from TGF-β-Induced FLRT3 Attenuation Is Essential for Cancer-Associated Fibroblast–Mediated Epithelial–Mesenchymal Transition in Colorectal Cancer

Supplementary Figure from TGF-β-Induced FLRT3 Attenuation Is Essential for Cancer-Associated Fibroblast–Mediated Epithelial–Mesenchymal Transition in Colorectal Cancer