Histone Acetyltransferase (HAT) P300/CBP Inhibitors Induce Synthetic Lethality in PTEN-Deficient Colorectal Cancer Cells through Destabilizing AKT

Abstract

PTEN, a tumor suppressor, is found loss of function in many cancers, including colorectal cancer. To identify the synthetic lethal compounds working with PTEN deficiency, we performed a synthetic lethality drug screening with PTEN-isogenic colorectal cancer cells. From the screening, we found that PTEN -/colorectal cancer cells were sensitive to anacardic acid, a p300/CBP histone acetyltransferase (HAT) inhibitor. Anacardic acid significantly reduced the viability of PTEN -/-cells not in PTEN +/+ cells via inducing apoptosis. Inhibition of HAT activity of p300/CBP by anacardic acid reduced the acetylation of histones at the promoter region and inhibited the transcription of Hsp70 family of proteins. The down-regulation of Hsp70 family proteins led to the reduction of AKT-Hsp70 complex formation, AKT destabilization and decreased the level of phosphorylated AKT at Ser473, all of which are vital for the survival of PTEN -/colorectal cells. The synthetic lethality effect of anacardic acid was further validated in tumor xenograft mice models, where PTEN -/-colorectal tumors showed greater sensitivity to anacardic acid treatment than PTEN +/+ tumors. These data suggest that anacardic acid induced synthetic lethality by inhibiting HAT activity of p300/CBP, thereby reducing Hsp70 transcription and destabilizing AKT in PTEN deficient colorectal cancer cells.

Anacardic Acids from Amphipterygium adstringens Confer Cytoprotection against 5-Fluorouracil and Carboplatin Induced Blood Cell Toxicity While Increasing Antitumoral Activity and Survival in an Animal Model of Breast Cancer

“…These effects have been linked to the capacity of these compounds to inhibit acetyl-transferases [ 16 , 18 , 32 , 33 ], which is a mechanism that is well characterized for 6SA. The myeloprotective effect and the protection of WBCs could be related to the previous immunomodulatory effect described for 6SA by our group and others [ 13 , 25 ], namely the ability of 6SA to induce the phosphorylation of kinases important for the proliferation of immune cells, particularly T lymphocytes and differentiated macrophages.…”

“…The biological effects of AAs include cytotoxic, antibacterial, and antiproliferative activities [ 6 , 10 , 11 , 12 , 13 , 14 ]. The main AA found in the bark of A. adstringens is 6-pentadecyl salicylic acid (6SA) ( Figure 1 ) , which is a well-characterized histone acetyltransferase inhibitor [ 15 , 16 ] that shows cytotoxic and antiproliferative activities in different cancer cell lines [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] and antineoplastic activity in xenografts in immunodeficient [ 19 , 24 ] and autologous cancer [ 25 ] models. 6SA also does not display cytotoxic effects in normal human peripheral blood mononuclear cells, in contrast to the most commonly used antineoplastic agents, which are cytotoxic to blood cells [ 17 ].…”

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

“…In the acetylated form, E2F1 recruits P300/CBP to the site of DNA damage, causing chromatin remodelling and facilitating DNA repair [ 34 ]. Drug-resistant PTEN −/− cancer cells treated with anacardic acid (AA) showed decreased viability and increased apoptosis [ 35 ]. In this experiment, the authors also observed Heat Shock Protein 70 (HSP70) and AKT1 reduction.…”

“…HSP70 is responsible for folding and refolding misfolded proteins and for the degradation of abnormal proteins. Downregulation of P300/CBP and the reduction of HSP70 causes AKT1 reduction on a transcriptional and post-translational level in PTEN −/− prostate cancer cells [ 35 ].…”

Radiation-reprogrammed glioma stem cells generate vascular-like cells to build a trophic niche driving tumor recurrence

“…It is well established that P300 plays a critical role in the DNA damage response by facilitating repair at sites of double strand breaks (DSB) through acetylation of histones and chromatin decompaction (42–45). Selective inhibition of P300 HAT activity using C646 small molecule inhibitor has been shown to inhibit cell growth and sensitize cells to DNA damaging agents in other cancers including melanoma (46) NSLC (47), colorectal (48), prostrate (49,50) and neuroblastoma (51). Consistent with these studies, we found that blocking P300 HAT activity resulted in significant reduction of chromatin accessibility and H3K27ac in vascular gene regions in response to radiation.…”