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We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and γH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90 days. Hepatocarcinogen treatment for 28 or 90 days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or γH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis.UBE2E2 downregulation was limited in GST-P-linked hepatocarcinogenesis.UBE2E2 downregulation may stabilize c-MYC, KDM4A and KMT5A in GST-P+ foci.c-MYC and KMT5A may facilitate PCNA-mediated cell proliferation in GST-P+ foci.KDM4A may be responsible for slowing down of DNA damage response in GST-P+ foci.UBE2E2 downregulation triggers and further promotes carcinogenic responses.