CRIP1 suppresses BBOX1‐mediated carnitine metabolism to promote stemness in hepatocellular carcinoma
CRIP1 suppresses BBOX1‐mediated carnitine metabolism to promote stemness in hepatocellular carcinoma
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DOI：
10.15252/embj.2021110218
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发表时间：
2022-07
期刊：
影响因子：
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通讯作者：
Jing Wang;Yan Zhou;Donghui Zhang;Weiyi Zhao;Yishi Lu;Chaoqun Liu;Wandie Lin;Yujie Zhang
中科院分区：
文献类型：
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作者：
Jing Wang;Yan Zhou;Donghui Zhang;Weiyi Zhao;Yishi Lu;Chaoqun Liu;Wandie Lin;Yujie Zhang
肉碱代谢被认为与肝细胞癌（HCC）的进展呈负相关，其具体分子机制尚未完全阐明。在这里，我们报道了很少被表征的富含半胱氨酸的蛋白 1 (CRIP1) 在 HCC 中表达上调，并与不良预后相关。此外，CRIP1 通过下调肉碱能量代谢来促进 HCC 癌症干细胞样特性。从机制上讲，CRIP1与BBOX1和E3连接酶STUB1相互作用，促进BBOX1泛素化和蛋白酶体降解，并导致肉碱下调。 BBOX1 在赖氨酸 240 处泛素化是 CRIP1 介导的肉毒碱代谢和癌症干细胞样特性的控制所必需的。此外，我们的数据表明，CRIP1 过表达细胞中乙酰肉碱的下调会减少 β-连环蛋白的乙酰化并促进 β-连环蛋白的核积累，从而促进癌症干细胞样特性。临床上，HCC组织中CRIP1蛋白水平较高的患者BBOX1水平较低，但核β-连环蛋白水平较高。总之，我们的研究结果将 CRIP1 确定为肉毒碱代谢和癌症干细胞样特性的新型上游控制因子，表明以 CRIP1/BBOX1/β-连环蛋白轴为靶点作为 HCC 治疗的一种有前景的策略。
Carnitine metabolism is thought to be negatively correlated with the progression of hepatocellular carcinoma (HCC) and the specific molecular mechanism is yet to be fully elucidated. Here, we report that little characterized cysteine‐rich protein 1 (CRIP1) is upregulated in HCC and associated with poor prognosis. Moreover, CRIP1 promoted HCC cancer stem‐like properties by downregulating carnitine energy metabolism. Mechanistically, CRIP1 interacted with BBOX1 and the E3 ligase STUB1, promoting BBOX1 ubiquitination and proteasomal degradation, and leading to the downregulation of carnitine. BBOX1 ubiquitination at lysine 240 is required for CRIP1‐mediated control of carnitine metabolism and cancer stem‐like properties. Further, our data showed that acetylcarnitine downregulation in CRIP1‐overexpressing cells decreased beta‐catenin acetylation and promoted nuclear accumulation of beta‐catenin, thus facilitating cancer stem‐like properties. Clinically, patients with higher CRIP1 protein levels had lower BBOX1 levels but higher nuclear beta‐catenin levels in HCC tissues. Together, our findings identify CRIP1 as novel upstream control factor for carnitine metabolism and cancer stem‐like properties, suggesting targeting of the CRIP1/BBOX1/β‐catenin axis as a promising strategy for HCC treatment.