C8orf76 Modulates Ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. Chromosome 8 open reading frame 76 (C8orf76), a novel gene located in the nucleus, is highly expressed in many tumor types. However, the specific mechanisms and functions of C8orf76 in HCC remain unclear. Here, we reported for the first time that C8orf76 gene expression levels were frequently upregulated in liver cancer and significantly correlated with HCC development. C8orf76 downregulation induced G1-S arrest and inhibited cell proliferation. Intriguingly, C8orf76 deficiency could accelerate erastin or sorafenib-induced ferroptosis through increasing lipid reactive oxygen species (ROS) levels. Moreover, although C8orf76 overexpression did not affect tumorigenesis under normal conditions, it increased resistance to lipid disturbance and ferroptosis triggered by erastin or sorafenib, which further facilitated HCC cell growth and tumor progression. Mechanistically, C8orf76 bound to the promoter region of the solute carrier family 7 member 11 (SLC7A11) gene and upregulated SLC7A11 transcriptionally. SLC7A11-dependent cystine import led to sufficient GSH synthesis and lipid peroxidation inhibition, thus accelerating tumor growth. Our study indicated that C8orf76 could be a novel marker for HCC diagnosis. In addition, a better comprehensive understanding of the potential role of C8orf76 in HCC helped us develop novel therapeutic strategies for this intractable cancer.

Utility of clinical metagenomics in diagnosing malignancies in a cohort of patients with Epstein-Barr virus positivity

“…Among the four patients, one was diagnosed with POEMS syndrome, and CNV analysis indicated a deletion of -19(mos) , the CNV analysis revealed a duplication of +8 in a patient with liver cancer, deletion of 6p22.2-p12.3(dup_23.5Mb) and 6p25.3-p22.2(del[mos]_26.6Mb) in a patient with gastric carcinoma, and a deletion of 6q11.1-q27(del[mos]_109.2Mb), 17p13.3-p11.1(del[mos]_22.3Mb) , duplication of 17q11.1-q25.3(dup[mos]_55.9Mb) and deletion of 19p13.3-p11(del[mos]_24.5Mb) in a patient with lymphoma ( Figures 2C–F ). Among these chromosomal variations, abnormalities of chromosome 17 has been found to be related to lymphoma, loss and gain of chromosome 6 has frequently been reported in gastric carcinoma, and upregulated expression of chromosome 8 has been found in liver cancer ( Jendiroba et al., 1995 ; Parada et al., 1998 ; Li et al., 2003 ; Kang et al., 2014 ; Li et al., 2022 ). These findings indicate the predictive and early diagnostic value of CNVs in malignant diseases.…”

Uncharacterized Proteins CxORFx: Subinteractome Analysis and Prognostic Significance in Cancers

“…By the way, an average proportion of GAs for known oncogenes (e.g., KIT , MYC , CTNNB1 , MDM2 and APC ) in the same pan-cancer cohort ranges from four to 9%. At least the function of genetically unstable C8orf76 is associated with cell proliferation [ 55 ], so amplification of the C8orf76 gene in cancers may be an independent risk factor of enhanced cell proliferation. According to the Cancer Gene Census portal, only the C15orf65 gene contains driver somatic mutations in primary mediastinal B-cell and Hodgkin’s lymphoma.…”

A Novel Ferroptosis-Related Signature for Prediction of Prognosis, Immune Profiles and Drug Sensitivity in Hepatocellular Carcinoma Patients

“…Furthermore, overexpression of NT5DC2 was reported to promote the proliferation of HCC cells in vitro and to facilitate tumor growth in vivo [ 41 ]. A growing body of evidence suggests that SLC711 facilitates proliferation of HCC cells and contributes to tumor advancement by inhibiting ferroptosis [ 10 , 42 , 43 ].…”