Pirarubicin reduces USP22 expression by inhibiting CREB‑1 phosphorylation in HeLa cells

Abstract

The expression of ubiquitin specific peptidase 22 (USP22) is upregulated in several types of cancer, and has been implicated in tumorigenesis. Pirarubicin (THP), an anthracycline antineoplastic drug, can induce apoptosis of several types of cancer cells. However, the molecular mechanisms underlying the action of THP remain to be elucidated. In the current study, treatment with THP induced HeLa cell apoptosis and decreased USP22 expression in a dose-and time-dependent manner. THP reduced the USP22 promoter-regulated luciferase activity, regardless of the mutation of transcriptional activator MYB or E3 ubiquitin-protein ligase SP1 binding sequences; however, this effect was abrogated by the mutation of cyclic AMP-responsive element-binding protein (CREB) binding sequence in HeLa cells. Furthermore, the inhibition on the USP22 promoter activity by THP was not affected by overexpression of CREB-1 in HeLa cells. Additionally, treatment with THP significantly decreased the phosphorylation of CREB-1 at ser133 in HeLa cells. Quantitative chromatin immunoprecipitation assay revealed that THP significantly inhibited the binding of CREB-1 to the USP22 promoter in HeLa cells. The present study demonstrated that THP decreased USP22 expression and promoted HeLa cell apoptosis partially by inhibiting the phosphorylation of CREB-1. The current results may provide novel insights into the molecular mechanisms underlying the pharmacological effect of THP on cancer cell apoptosis.

Inhibition of miR-15a-5p Promotes the Chemoresistance to Pirarubicin in Hepatocellular Carcinoma via Targeting eIF4E

“…As a DNA embedment agent, THP has been shown to reduce tumor activity in hepatocellular carcinoma patients [ 13 ]. Moreover, THP has also been found to possess good inhibitory effects on many kinds of tumors, such as breast cancer and cervical cancer [ 14 , 31 ]. In spite of these, the clinical application of THP is limited due to chemosensitivity resistance, which is the main cause of death in cancer patients [ 32 ].…”

Targeted hollow pollen silica nanoparticles for enhanced intravesical therapy of bladder cancer

“…THP has been reported capable of inducing cell apoptosis. 41 After treatment with THP@CHPS, THP@HPS, THP@HS NPs or free THP for 24 h, the apoptotic percentages of MB49 and 3T3 cells were analyzed by flow cytometry using Annexin V-FITC and PI. For MB49 cells, free THP, THP@HS, THP@HPS and THP@CHPS NPs induced 5.4, 10.5, 10.8 and 19.0% of early apoptotic cells, respectively, and 4.4, 5.0, 10.0 and 7.8% of late apoptotic cells, respectively (Fig.…”

Deubiquitination in prostate cancer progression: role of USP22

“…However, till now, no such specific inhibitor has been validated to target USP22. Recently, Pirarubicin (4’-O-tetrahydropyranyl doxorubicin, THP), an anthracycline (analogue of another chemotherapeutic agent known as doxorubicin), has been shown to inhibit USP22 expression in a condition-specific manner [ 87 ] . Reports indicated that protein kinase A (PKA), protein kinase B or mitogen activated kinase-mediated phosphorylation of CREB-1 bind and activate the USP22 promoter for its synthesis.…”