The p300 inhibitor A-485 exerts antitumor activity in growth hormone pituitary adenoma

Background: Growth hormone pituitary adenoma (GHPA) is a major subtype of pituitary adenoma. It can lead to progressive somatic disfigurement, multiple complications and even increased mortality. The efficacy of the current treatments is limited; thus, a novel pharmacological treatment is urgently needed. As a histone acetyltransferase (HAT) coactivator, p300 can regulate the transcription of several genes that are crucial for pituitary adenoma tumorigenesis and progression. However, the role of p300 and its catalytic inhibitor in GHPA is still unclear.

Methods: The expression of p300 was detected in GHPA and normal pituitary tissues. Genetic knockdown was performed by siRNA. The efficacy of the p300 inhibitor A-485 in the cell cycle, proliferation, apoptosis and hormone secretion was investigated by flow cytometry, ELISAs, western blotting and qRT-PCR. RNA sequencing, bioinformatic analysis and subsequent validation experiments were performed to reveal the potential biological mechanism of A-485.

Results: High expression of p300 was found in GHPA tissues compared with normal pituitary tissues. Knockdown of p300 inhibited cell proliferation and clone formation. Treatment with A-485 suppressed cell growth and inhibited the secretion of GH in vitro and in vivo. Further mechanistic studies showed that A-485 could downregulate the expression or activity of several oncogenes, such as genes in the Pttg1, c-Myc, cAMP and PI3K/AKT/mTOR signaling pathways, which are crucial for pituitary adenoma tumorigenesis and progression.

Conclusions: In this study, our findings demonstrate that inhibition of HAT p300 by its selective inhibitor A-485 is a promising therapy for GHPA.

Related Products

Cat.No.	Product Name	Information
S8740	A-485	A-485 is a potent, selective and drug-like p300/CBP catalytic inhibitor with an IC50 of 0.06 μM for p300 HAT. It is selective over BET bromodomain proteins and >150 non-epigenetic targets.

Related Targets

Histone Acetyltransferase Epigenetic Reader Domain