Journal
EMBO JOURNAL
Volume 41, Issue 15, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021110218
Keywords
cancer stemness; carnitine metabolism; cysteine-rich intestinal protein 1; gamma-butyrobetaine hydroxylase 1; hepatocellular carcinoma
Categories
Funding
- National Natural Science Foundation of China [81972813]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515010974, 2020A1515011389, 2021A1515111190]
- Beijing Xisike Clinical Oncology Research Foundation [Y-Roche2019/2-0025]
Ask authors/readers for more resources
The study reveals that CRIP1 is upregulated in HCC and associated with poor prognosis. It promotes HCC cancer stem-like properties by downregulating carnitine energy metabolism. The findings suggest that targeting the CRIP1/BBOX1/beta-catenin axis may be a promising strategy for HCC treatment.
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/beta-catenin axis as a promising strategy for HCC treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available