New Research Supports HERC5 as a Potential Metastasis Suppressor Gene in NSCLC

By: Vanessa A. Carter, BS
Posted: Friday, May 17, 2024

Among cancer-related deaths in patients with non–small cell lung cancer (NSCLC), metastasis is the leading cause. Harriet Wikman, PhD, of the University Medical Center Hamburg-Eppendorf, Germany, and colleagues previously demonstrated that low HERC5 expression may predict early tumor dissemination and a poor prognosis in those with NSCLC. Their current study, published in the Journal of Experimental & Clinical Cancer Research, provided new evidence that HERC5—one of six HERC proteins—appears to act as a metastasis suppressor gene.

“[HERC5] loss causes cells to switch from an oxidative to a more glycolytic state, indicative of the Warburg effect, thereby promoting cell migration and metastatic growth,” the investigators concluded. “Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.”

NSCLC HEK293T cell-line models were transfected with either the LEGO-iG2-HERC5-HA or LEGO-iG2-HA plasmid to induce HERC5 overexpression. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) technology was used to generate A549 HERC5 knockout cells. Cells were evaluated for colony formation potential, migration, wound healing, anchorage-independent growth, and cell proliferation. Early tumor cell dissemination was assessed using these cell lines in zebrafish experiments and intracardiac injections in nude mice.

NSCLC cells demonstrating low HERC5 expression were observed to have increased invasive and malignant properties. Of note, increased metastasis formation and dissemination were identified—particularly in the brain—in both the zebrafish and xenograft nude mice models. Additionally, when HERC5 levels were high, mass spectrometry enrichment clustering data identified an increase in mitochondrial proteins in vitro. It was noted that the loss of HERC5 seemed to induce improved survival and adaptation of cells under prolonged inhibition of oxidative phosphorylation.

Disclosure: The study authors reported no conflicts of interest.

Journal of Experimental & Clinical Cancer Research

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