Int J Biol Sci 2020; 16(11):1774-1784. doi:10.7150/ijbs.42197

Research Paper

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

Yifan Liu, Eun Ju Yang, Changxiang Shi, Pui Kei Mou, Baoyuan Zhang, Changjie Wu, Junfang Lyu, Joong Sup Shim

Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, 999078, Macau

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Citation:
Liu Y, Yang EJ, Shi C, Mou PK, Zhang B, Wu C, Lyu J, Shim JS. Histone Acetyltransferase (HAT) P300/CBP Inhibitors Induce Synthetic Lethality in PTEN-Deficient Colorectal Cancer Cells through Destabilizing AKT. Int J Biol Sci 2020; 16(11):1774-1784. doi:10.7150/ijbs.42197. Available from http://www.ijbs.com/v16p1774.htm

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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.

Keywords: PTEN, Synthetic lethality, Histone acetyltransferases, Anacardic acid, AKT, Hsp70