OBJECTIVE: To explore the effect and potential mechanism of T-LAK cell-originated protein kinase (TOPK) on autophagy in cutaneous squamous cell carcinoma (cSCC). METHODS: Human cSCC cancer tissue and paracancerous tissue samples were collected clinically; immunohistochemistry was used to detect the expression of TOPK, nuclear factor B p65 (NF-B p65), phosphorylated nuclear factor B inhibitor (p-IB), Beclin-1, and microtubule-associated protein 1 light chain 3 (LC3) in cSCC tissue; and immunofluorescence was adopted to detect the coexpression of NF-B p65, p-IB, and TOPK in cSCC tissue. After TOPK silencing or overexpression, SCL-1 and A431 cells were treated with PDTC and 3-MA, respectively. RT-qPCR and Western Blot were used to detect the mRNA and protein expressions of histone deacetylase 1 (HDAC1) in TOPK-silenced/overexpressing cells. Western Blot was performed to detect the protein expressions of NF-B p65, p-p65, IB, p-IB, Beclin-1, and LC3 in each group. Transwell and scratch healing experiments were used to detect the ability of cells to invade and migrate. The formation of autophagosomes in each group was observed by TEM. RESULTS: Compared with adjacent tissues, TOPK, NF-B p65, p-IB, Beclin-1, and LC3 were highly expressed in cSCC cancer tissues; TOPK and NF-B p65 were coexpressed; and TOPK and p-IB were expressed in cSCC cancer tissues both increased. The mRNA and protein levels of TOPK in human cSCC cells were significantly higher than those in human normal skin HaCaT cells. After TOPK knockout, the expression of HDAC1, p-IB/IB, NF-B p65, p-p65, Beclin-1, LC3II/I proteins, cell invasion, and migration abilities were significantly reduced, and fewer autophagosomes were observed. Treatment with PDTC and 3-MA significantly downregulated NF-B pathway protein activity and autophagy level and reduced cell migration and invasion ability. CONCLUSION: TOPK promotes the malignant progression of cSCC by upregulating HDAC1 to activate the NF-B pathway and promote autophagy.