Ren Guowen, Chen Jinghong, Pu Yue, Yang Eun Ju, Tao Shishi, Mou Pui Kei, Chen Li-Jie, Zhu Wenli, Chan Kin Long, Luo Guanghui, Deng Chuxia, Shim Joong Sup
Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
Central laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Int J Biol Sci. 2024 Mar 11;20(6):1978-1991. doi: 10.7150/ijbs.91867. eCollection 2024.
Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in CRC. Further, BETi selectively and dose-dependently suppressed the growth of CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.
PTEN肿瘤抑制因子的缺失是结直肠癌（CRC）发展过程中的一个重要事件，也是治疗开发的一个靶点。本研究报告称，溴结构域和额外末端基序（BET）是CRC中PTEN的合成致死伴侣。BET抑制（BETi）在CRC中选择性地诱导G1期细胞周期停滞和凋亡。此外，BETi选择性地且剂量依赖性地抑制了小鼠体内CRC肿瘤异种移植瘤以及患者来源类器官的生长。机制上，PTEN缺陷的CRC细胞提高了细胞质中p21的水平，该p21在苏氨酸145处被AKT过度磷酸化。BETi抑制了PTEN缺陷的CRC细胞中AKT的激活，随后苏氨酸145处p21磷酸化减少，从而促进其核转位。此外，BETi抑制了MYC水平，这反过来又增加了细胞核中总p21水平。磷酸模拟p21突变体（T145D）的过表达显著挽救了BETi对PTEN缺陷的CRC的作用。这些结果表明，BETi对p21具有双重作用：通过抑制MYC提高p21水平，并通过抑制AKT将致癌性（细胞质）p21转化为肿瘤抑制性（细胞核）p21。综上所述，本研究确定了PTEN与BET之间的合成致死相互作用，并为PTEN缺失的CRC提供了一个潜在的可操作靶点。
