Oral squamous cell carcinoma (OSCC), which is typically preceded by oral leukoplakia (OL), is a common malignancy with poor prognosis. However, the signaling molecules governing this progression remain to be defined. Based on microarray analysis of genes expressed in OL and OSCC samples, we discovered that the long non-coding RNA IFITM4P was highly expressed in OSCC, and ectopic expression or knockdown of IFITM4P resulted in increased or decreased cell proliferation in vitro and in xenografted tumors, respectively. Mechanistically, in the cytoplasm IFITM4P acted as a scaffold to facilitate recruiting SASH1 to bind and phosphorylate TAK1 (Thr187), and in turn to increase the phosphorylation of nuclear factor κB (Ser536) and concomitant induction of PD-L1 expression, resulting in activation of an immunosuppressive program that allows OL cells to escape anti-cancer immunity in cytoplasm. In nucleus, IFITM4P reduced Pten transcription by enhancing the binding of KDM5A to the Pten promoter, thereby upregulating PD-L1 in OL cells. Moreover, mice bearing tumors with high IFITM4P expression had notable therapeutic sensitivity to PD-1 monoclonal antibody (mAb) treatment. Collectively, these data demonstrate that IFITM4P may serve as a new therapeutic target in blockage of oral carcinogenesis, and PD-1 mAb can be an effective reagent to treat OSCC.

Significance: The etiology of heart disorders remains poorly understood. In this paper, we show for the first time to our knowledge, that protein palmitoylation plays a critical role in heart structure and function. We demonstrate that Aph2 (Ablphilin 2) is a palmitoyl transferase and identify phospholamban, a cardiomyopathy disease gene, as a substrate. Some of the heart defects of anAph2^−/−mouse can be rescued by phospholamban ablation. In addition, the present study reveals critical roles for protein palmitoylation in embryonic/postnatal survival and eye development.

Snail is a prominent epithelial–mesenchymal transition (EMT) transcription factor and promotes metastasis. However, Snail protein is unstable and is quickly degraded through ubiquitination-mediated proteasome pathway. Deubiquitinases prevent Snail degradation by regulating the ubiquitination-mediated hydrolysis process. Our studies demonstrate that a deubiquitinating enzyme (DUB) family member, USP37, can deubiquitinate Snail and prevent degradation of Snail. USP37 is co-localized with Snail in the nucleus. Biologically, upregulated expression of USP37 promotes lung cancer cell migration, while depletion of Snail abolishes the effect of USP37. These data demonstrate that USP37 is a Snail-specific deubiquitinase and also indicate a potential therapeutic target for metastasis.

DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis. On genotoxic stress, Atm phosphorylates BMPs-activated Smad1 in the nucleus on S239, which disrupts Smad1 interaction with protein phosphatase PPM1A, leading to enhanced activation and upregulation of Smad1. Smad1 then interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced Smad1 S239 phosphorylation, and Smad1 mutations causing S239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BMP-Smad1 signalling participates in the DNA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BMP-Smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.