Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation

Abstract

Although p53 is intact in most cases of retinoblastoma, it is largely inactivated by the ubiqutin-proteasome system through interaction with murine double minute 2 (MDM2) and murine double minute X (MDMX). The present study showed that the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and depsipeptide (FK228) synergistically enhanced ionizing radiation (IR)-induced apoptosis, associated with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Y79 and WER1-Rb1 human retinoblastoma cells. Both VPA and FK228 enhanced IR-induced phosphorylation of histone H2AX on Ser139 preceding apoptosis. Exposure of cells to IR in the presence of VPA or FK228 induced the accumulation of p53 acetylated at Lys382 and phosphorylated at Ser46 through the reduction of binding affinity with MDM2 and MDMX. These results suggest that acetylation of p53 by HDAC inhibitors is a promising new therapeutic target in refractory retinoblastoma.

Valproic Acid Regulates HR and Cell Cycle Through MUS81-pRPA2 Pathway in Response to Hydroxyurea

“…In recent years, histone deacetylase inhibitors (HDACi) have been widely studied as a possible adjuvant or neoadjuvant to chemotherapy (3,4). Specifically, valproic acid (VPA) -a class I and II HDACi used in the treatment of epilepsy and as a mood stabilizer for bipolar disorder (5)(6)(7) -has demonstrated the ability to inhibit the growth of breast cancer cells while also exhibiting a radio sensitizing effect at a safe therapeutic dose (6,(8)(9)(10)(11)(12)(13). Hydroxyurea (HU), is a common chemotherapeutic for hematological malignancies such as polycythemia vera, melanoma, and head and neck cancer (14)(15)(16)(17).…”

HDAC-an important target for improving tumor radiotherapy resistance

“…But the effect is significantly weaker than that of mutP53 tumorsHDAC3 can inhibit the acetylation of P53 and promote the signal activity of NF-kB, thereby inhibiting cell cycle arrest and apoptosis ( 133 , 134 ). In retinoblastoma, HDACi can simultaneously promote the acetylation, phosphorylation, and nuclear relocation of P53, activate P53, up-regulate Bax/Fas, and enhance radiosensitivity ( 135 ). In mouse endometrial carcinoma, the selective HDAC SIRT1 inhibitor significantly promotes the degradation of P53 negative regulator, mouse double minute 2, prevents its binding with P53, acetylates P53, enhances the activity of P53, promotes the expression of Fas/Bax, and causes cell apoptosis ( 136 ).…”