期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 16, 期 11, 页码 1774-1784出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.42197
关键词
PTEN; Synthetic lethality; Histone acetyltransferases; Anacardic acid; AKT; Hsp70
资金
- Multi-Year Research Grant of the University of Macau [MYRG2017-00176-FHS, MYRG2019-00116-FHS]
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.
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