A Bhas42 cell transformation assay is a method used to detect the tumour-promoting activities of chemicals. However, the mechanisms underlying tumour transformations mediated by non-genotoxic carcinogens (NGCs) are poorly understood. This study aimed to examine the correlation between 12--tetradecanoylphorbol 13-acetate (TPA) or mezerein and the initiation of tumourous transformations by epigenetic regulation in Bhas42 cells. We found that TPA and mezerein prompted tumourous transformations by stimulating cell proliferation and migration in Bhas42 cells. Furthermore, we observed alterations in the expression levels of 134 genes, with 87 genes being upregulated and 47 genes being downregulated, following exposure to either TPA or mezerein. Among the differentially regulated genes, we identified 17 upregulated genes and 8 downregulated genes corresponding to differentially expressed genes in TNM [primary tumour (T), regional nodes (N), and metastasis (M)]. Importantly, we found that TPA and mezerein triggered the expression of Hmga2 and Ezh2 by loss of miRNA let-7 (miR let-7) in Bhas42 cells. Finally, the microRNA (miRNA) mimic of let-7 prevented the TPA- and mezerein-induced activation of Hmga2 and Ezh2 in Bhas42 cells. Our findings reveal a connection between tumourous transformations and the epigenetic regulator miR let-7 in NGCs, such as TPA and mezerein in Bhas42 cells. This highlights miR let-7 as a promising therapeutic target for mitigating tumourous transformations induced by NGCs.