PDF(Pubmed)
Abstract：
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 PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 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.
摘要：
PTEN肿瘤抑制因子的缺失是结直肠癌（CRC）发展过程中的重要事件，并且是治疗开发的目标。这项研究报道，溴结构域和末端外基序（BET）是CRC中PTEN的合成致死伴侣。BET抑制（BETi）选择性诱导PTEN-/-CRC中的G1细胞周期停滞和凋亡。Further,BETi选择性和剂量依赖性地抑制小鼠和患者来源的类器官中PTEN-/-CRC肿瘤异种移植物的生长。机械上,PTEN缺陷型CRC细胞提高了在Thr145被AKT过度磷酸化的细胞质p21CIP1/WAF1的水平。BETi抑制PTEN缺陷型CRC细胞中的AKT激活，随后在Thr145处p21磷酸化减少,从而促进其核易位。此外,BETi抑制了MYC水平，这反过来又增加了细胞核中的总p21水平。磷酸化模拟p21突变体（T145D）的过表达显着挽救了BETi对PTEN缺陷性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的水平，并通过抑制AKT将致癌（细胞质）p21转化为肿瘤抑制（核）p21。一起来看,这项研究确定了PTEN和BET之间的合成致死相互作用，并为具有PTEN丢失的CRC提供了潜在的可操作目标。
