Disruption in mucins (MUCs) is involved in cancer development and metastasis and is thus used as a biomarker. Non-small cell lung carcinoma (NSCLC) is characterized by heterogeneous genetic and epigenetic alterations. Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the two primary subtypes of NSCLC that require different therapeutic interventions. Here, we report distinct expression and epigenetic alterations in mucin 22 (MUC22), a new MUC family member, in LUSC vs. LUAD. In lung cancer cell lines and tissues, MUC22 was downregulated in LUSC (MUC[22.sup.Low]) but upregulated in LUAD (MUC[22.sup.High]) with co-expression of MUC21. The aberrant expression of MUC22 was inversely correlated with its promoter hypermethylation in LUSC and hypomethylation in LUAD cells and tissues, respectively. Decreased MUC22 expression in NSCLC cell lines was restored upon treatment with epigenetic modifiers 5-aza-2'-deoxycytidine (5-Aza) or trichostatin A (TSA), accompanied by reduction in global protein level of histone deacetylase 1 (HDAC1) but increased enrichment of histone H3 lysine 9 acetylation (H3K9ac) specifically in the MUC22 promoter in the SK-MES-1 cell line. MUC22 knockdown increased the growth and motility of lung cancer cells and an immortalized human bronchial epithelial BEAS-2B cell line via NF-[kappa]B activation. Clinically, MUC[22.sup.Low] in LUSC and MUC[22.sup.High] in LUAD were shown to be indicators of unfavorable overall survival for patients with early cancer stages. Our study reveals that changes in MUC22 expression due to epigenetic alterations in NSCLC may have important biological significance and prognostic potential in LUSC when compared to LUAD. Thus, MUC22 expression and epigenetic alterations may be used for molecular subtyping of NSCLC in precision medicine. Key words: mucin 22, non-small cell lung carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, differential expression, epigenetic alterations, DNA methylation, histone acetylation, tumor heterogeneity, biomarker, molecular subtyping