Abstract
In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis. In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1–S transition and metaphase–anaphase transition. The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition. In conclusion, the USP24 level was decreased during the early stage of cancer and the mitotic stage of the cell cycle to regulate its substrates p300, Bax, E2F4 and securin, resulting in decreased cell apoptosis and increased cell cycle progression and, thus, cancer formation.
Highlights
Ubiquitin-specific peptidases (USPs) belong to a large family of cysteine proteases and are deubiquitinating enzymes that recognize and remove ubiquitin from proteins.[1]
We found that the phosphorylation of ubiquitin-specific peptidase 24 (USP24) by CDK1- or Epidermal growth factor (EGF)-mediated kinase activity decreased the USP24 level
Kras or EGFR, USP24 downregulation positively affected the efficacy of lung cancer formation (Figure 9)
Summary
Ubiquitin-specific peptidases (USPs) belong to a large family of cysteine proteases and are deubiquitinating enzymes that recognize and remove ubiquitin from proteins.[1]. Knockdown of USP24 decreased the Bax and caspase-3 levels; these protein levels were increased in GFP-USP24-expressing cells, no alterations were observed in the Bax mRNA level (Figure 2B; Supplementary Figure 2B). The USP24 ubiquitination signal was increased during the mitotic stage (Figure 5E; Supplementary Figure 4F), implying that the decrease in the USP24 level during mitosis might be due to the enhancement of USP24 degradation. Cdc[20] could interact with USP24 when these residues were phosphorylated, implying that the decrease in USP24 during mitosis might be important for cell cycle progression and cancer cell proliferation (Figure 7G). 2938 level and the substrates identified in this study, suggesting that USP24 might regulate p300, Bax, E2F4 and securin levels to regulate apoptosis and cell cycle progression, resulting in cancer formation. These results indicated that USP24 expression was downregulated in lung adenocarcinoma
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