COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma

Abstract

The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.

COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers

“…An increasing body of evidence from recent decades has supported that bioenergetic homeostasis is crucial for tumorigenesis and/or the progression of many cancer types, including HCC and CRCs [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 24 ]. COX5B has been reported as a growth-promoting gene that modulates downstream pathways in response to the induced bioenergetic alterations in HCC, breast cancer, and glioma, but its role in CRCs remains unknown [ 24 , 29 , 30 , 31 ]. As such, clinical associations and experimental assays were conducted to investigate the role and potential mechanism of action of COX5B in CRCs.…”

“…Recently, two distinct reference datasets were comparatively analyzed, which revealed that several subunits of COX were significantly elevated or downregulated in HCC. Only COX subunit 5B (COX5B) harbored an oncogene-like property, as HCC patients with higher COX5B expression showed poorer clinical outcomes [ 24 ]. Moreover, a signaling cascade composed of AMPK-UHMK1-ERK operating through COX5B-mediated bioenergetic alterations was also demonstrated, and further reinforcing the hypothesis that COX5B has an oncogene-like property.…”

GNAi2/gip2-Regulated Transcriptome and Its Therapeutic Significance in Ovarian Cancer

“…COX5B gene encodes cytochrome c oxidase, and it is another critical component of the mitochondrial respiratory chain. Overexpression of COX5B is associated with a poor prognosis in many cancers [53,54]. The observation that these critical nodes are part of the gene cluster involved in mitochondrial oxidative phosphorylation gains further significance in light of the recent findings that mitochondrial oxidative phosphorylation is upregulated in many cancers including ovarian cancer [55][56][57].…”

SYNE1 Exonic Variant rs9479297 Contributes to Concurrent Hepatocellular and Transitional Cell Carcinoma Double Primary Cancer

“…The IHC staining was conducted as described previously [ 14 ]. The recombinant anti-SYNE1 antibody (Abcam, Cambridge, UK, ab192234) was used for SYNE1 staining.…”

“…The wound healing experiment was performed by using a wound healing assay kit (Abcam, ab242285) according to the manufacturer’s instructions. The procedures for transwell assay (Corning, Corning, NY, USA, CLS3422) were conducted as previously described [ 14 ].…”