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. image The molecular details of how carnitine energy metabolism regulates liver cancer remain poorly understood. This work identifies zinc finger protein CRIP1 as upstream control factor for carnitine synthesis and oncogenic WNT/beta‐catenin signaling in hepatocellular carcinoma (HCC), suggesting new potential therapeutic avenues. CRIP1 correlates with poor survival in HCC patient samples. CRIP1 downregulates carnitine metabolism and promotes cancer stem‐like properties in HCC cell lines. CRIP1 facilitates interaction of ubiquitin ligase STUB1 and carnitine synthesis enzyme BBOX1, enhancing BBOX1 ubiquitination and proteasomal degradation. CRIP1 overexpression decreased acetylcarnitine levels and beta‐catenin acetylation, promoting nuclear beta‐catenin accumulation. Targeting the CRIP1/BBOX1/beta‐catenin axis impairs HCC in xenograft assays.