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

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

doi:10.7150/ijbs.42197

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

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

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. https://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

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APA

Liu, Y., Yang, E.J., Shi, C., Mou, P.K., Zhang, B., Wu, C., Lyu, J., Shim, J.S. (2020). Histone Acetyltransferase (HAT) P300/CBP Inhibitors Induce Synthetic Lethality in PTEN-Deficient Colorectal Cancer Cells through Destabilizing AKT. International Journal of Biological Sciences, 16(11), 1774-1784. https://doi.org/10.7150/ijbs.42197.

ACS

Liu, Y.; Yang, E.J.; Shi, C.; Mou, P.K.; Zhang, B.; Wu, C.; Lyu, J.; Shim, J.S. 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.

NLM

CSE

Liu Y, Yang EJ, Shi C, Mou PK, Zhang B, Wu C, Lyu J, Shim JS. 2020. Histone Acetyltransferase (HAT) P300/CBP Inhibitors Induce Synthetic Lethality in PTEN-Deficient Colorectal Cancer Cells through Destabilizing AKT. Int J Biol Sci. 16(11):1774-1784.

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