CRIP1 suppresses BBOX1-mediated carnitine metabolism to promote stemness in hepatocellular carcinoma.

Abstract

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.

• Authors: Jing Wang, Yan Zhou, Donghui Zhang, Weiyi Zhao, Yishi Lu, Chaoqun Liu, Wandie Lin, Yujie Zhang, Kunling Chen, Hui Wang, Liang Zhao
• Journal: The EMBO journal (EMBO J) Vol. 41 Issue 15 Pg. e110218 (08 01 2022) ISSN: 1460-2075 [Electronic] England
• PMID: 35775648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors.

Chemical References

• CRIP1 protein, human
• Carrier Proteins
• LIM Domain Proteins
• beta Catenin
• BBOX1 protein, human
• gamma-Butyrobetaine Dioxygenase
• STUB1 protein, human
• Ubiquitin-Protein Ligases
• Carnitine

Topics

• Carcinoma, Hepatocellular (metabolism)
• Carnitine
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• LIM Domain Proteins (metabolism)
• Liver Neoplasms (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• beta Catenin (genetics, metabolism)
• gamma-Butyrobetaine Dioxygenase (metabolism)