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. 2024 Dec;56(6):645-655.
doi: 10.1007/s10863-024-10039-6. Epub 2024 Sep 30.

PRKN-mediated the ubiquitination of IQGAP3 regulates cell growth, metastasis and ferroptosis in early-onset colorectal cancer

Gun Chen  1 , Linghua Cong  2 , Chijiang Gu  3 , Ping Li  2
Affiliations

PRKN-mediated the ubiquitination of IQGAP3 regulates cell growth, metastasis and ferroptosis in early-onset colorectal cancer

Gun Chen et al. J Bioenerg Biomembr. 2024 Dec.

Abstract

High IQ motif-containing GTPase activating protein 3 (IQGAP3) expression is considered to be associated with poor prognosis of colorectal cancer (CRC). However, its role in early-onset CRC (EOCRC) progress is unclear. The mRNA and protein levels of IQGAP3 and Parkin (PRKN) were examined by qRT-PCR and western blot. Cell proliferation, apoptosis and metastasis were determined by CCK8 assay, EdU assay, flow cytometry and transwell assay. ROS, MDA, GSH, Fe2+, ACSL4 and SLC7A11 levels were detected to assess cell ferroptosis. The interaction between PRKN and IQGAP3 was assessed by Co-IP assay and ubiquitination assay. Xenograft tumor models were constructed to explore the effect of PRKN and IQGAP3 on the tumorigenesis in vivo. IQGAP3 was upregulated, while PRKN was downregulated in EOCRC tissues and cells. IQGAP3 knockdown inhibited CRC cell proliferation, migration and invasion, while enhanced apoptosis and ferroptosis. PRKN ubiquitinated IQGAP3 to promote its degradation. PRKN overexpression suppressed CRC cell growth, metastasis and promoted ferroptosis, while these effects were reversed by upregulating IQGAP3. In animal study, upregulation of PRKN reduced CRC tumorigenesis by decreasing IQGAP3 expression in vivo. IQGAP3, ubiquitinated by PRKN, promoted EOCRC progression by enhancing cell proliferation, metastasis, repressing apoptosis and ferroptosis, which provided a novel target for EOCRC treatment.

Keywords: Early-onset CRC; Ferroptosis; IQGAP3; PRKN; Ubiquitination.

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Conflict of interest statement

Declarations. Ethical approval and consent to participate: Each patient signed informed consent, and this study was approved by the Ethics Committee of the Affiliated People’s Hospital of Ningbo University. Animal experiments were approved by the Animal Ethics Committee of the Affiliated People’s Hospital of Ningbo University. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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