Fructose-bisphosphate aldolase A (ALDOA) is a key enzyme in glycolysis and is responsible for catalyzing the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate. ALDOA contributes to various cellular functions such as muscle maintenance, regulation of cell shape and mobility, striated muscle contraction, actin filament organization and ATP biosynthetic process. Here, we reported that ALDOA is a highly expressed in lung squamous cell carcinoma (LSCC) and its expression level is correlated with LSCC metastasis, grades, differentiation status and poor prognosis. Depletion of ALDOA expression in the lung squamous carcinoma NCI-H520 cells reduces the capabilities of cell motility and tumorigenesis. These data suggest that ALDOA could be a potential marker for LSCC metastasis and a therapeutic target for drug development.

Transcriptional repressor Snail is a master regulator of epithelial–mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. Cancer Res; 74(16); 4353–63. ©2014 AACR.

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.