ST6GalNAc‐I promotes lung cancer metastasis by altering MUC5AC sialylation. Issue 7 (1st May 2021) - Lakshmanan, Imayavaramban
Abstract : Lung cancer (LC) is the leading cause of cancer‐related mortality. However, the molecular mechanisms associated with the development of metastasis are poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models Kras G12D/+ ; Trp53 R172H/+ ; Ad‐Cre (KPA) and Kras G12D/+ ; Ad‐Cre (KA). Survival analysis showed significantly ( P = 0.0049) shorter survival in KPA tumor‐bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of N‐acetylgalactosaminide alpha‐2, 6‐sialyltransferase 1 (St6galnac‐I) in KPA compared to KA tumors. ST6GalNAc‐I is an O‐glycosyltransferase, which catalyzes the addition of sialic acid to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins, such as mucins. Ectopic expression of species‐specific p53 mutants in the syngeneic mouse and human LC cells led to increased cell migration and high expression of ST6GalNAc‐I, STn, and MUC5AC. Immunoprecipitation of MUC5AC in the ectopically expressing p53 R175H cells exhibited higher affinity toward STn. In addition, ST6GalNAc‐I knockout (KO) cells also showed decreased migration, possibly due to reduced glycosylation of MUC5AC as observed by low STn on the glycoprotein. Interestingly, ST6GalNAc‐I KO cells injected mice developed less liver metastasis ( P = 0.01) compared to controls, while colocalization of MUC5AC and STn was observed in the liver metastatic tissues of control mice. Collectively, our findings support the hypothesis that mutant p53 R175H mediates ST6GalNAc‐I expression, leading to the sialyation of MUC5AC, and thus contribute to LC liver metastasis. Abstract : In the presence of mutant p53 R175H, ST6GalNAc‐I mediates MUC5AC sialylation that increases the aggressiveness of lung adenocarcinoma (LUAD). MUC5AC sialylation is required for integrin β4 interaction that induces angiogenesis and liver metastasis. Hence, targeting the ST6GalNAc‐I/MUC5AC could prevent LUAD metastasis.