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In Drosophila, it was reported that PP6 suppresses tumorigenicity of mutant RAS. However, the information how PP6 regulates oncogenic RAS in mammals is limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K\u2010rasG12D)\u2010 and KP (K\u2010rasG12D + Trp53\u2010deficient)\u2010inducible mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expressions between tissues of Ppp6c\u2010deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then analyzed genes commonly altered by Ppp6c deficiency, with or without Trp53 deficiency, and identified a group concentrated in KEGG database pathways defined as \u2018Pathways in Cancer\u2019 and \u2018Cytokine\u2010cytokine receptor interaction\u2019. We then evaluated signals downstream of oncogenic RAS and those regulated by PP6 substrates and found that in the presence of K\u2010rasG12D, Ppp6c deletion enhanced the activation of the ERK\u2010ELK1\u2010FOS, AKT\u20104EBP1, and AKT\u2010FOXO\u2010CyclinD1 axes. Ppp6c deletion combined with K\u2010rasG12D also enhanced DNA double\u2010strand break (DSB) accumulation and activated NF\u03baB signaling, upregulating IL\u20101\u03b2, COX2, and TNF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.3962","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T10:03:55Z","timestamp":1624010635000},"page":"4451-4464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<i>Ppp6c<\/i> deficiency accelerates <i>K\u2010ras<\/i><i><sup>G12D<\/sup><\/i>\u2010induced tongue carcinogenesis"],"prefix":"10.1002","volume":"10","author":[{"given":"Kazuhiro","family":"Kishimoto","sequence":"first","affiliation":[{"name":"Division of Cancer Chemotherapy Miyagi Cancer Center Research Institute Miyagi Japan"},{"name":"Division of Cancer Molecular Biology Tohoku University School of Medicine Miyagi Japan"},{"name":"Department of Head and Neck Surgery Kanazawa Medical 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