SPATA20 deficiency enhances the metastatic and angiogenic potential of cancer cells by promoting HIF-1α synthesis

Sanga Choi; Seongkyeong Yoo; Miyeon Jeon; Soohyun Park; Yunsup Choi; Jiyeon An; Sungmi Jeon; Mingyu Lee; Jang-Hyuk Yun; Jong-Wan Park; Iljin Kim

doi:10.62347/EHQK4921

SPATA20 deficiency enhances the metastatic and angiogenic potential of cancer cells by promoting HIF-1α synthesis

Am J Cancer Res. 2024 Feb 15;14(2):727-743. doi: 10.62347/EHQK4921. eCollection 2024.

Authors

Sanga Choi^{1

2}, Seongkyeong Yoo^{1

2}, Miyeon Jeon^{1

2}, Soohyun Park^{1

2}, Yunsup Choi^{1

2}, Jiyeon An^{1

2}, Sungmi Jeon³, Mingyu Lee⁴, Jang-Hyuk Yun⁵, Jong-Wan Park⁶, Iljin Kim^{1

2}

Affiliations

¹ Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University College of Medicine Incheon 22212, South Korea.
² Research Center for Controlling Intercellular Communication, Inha University College of Medicine Incheon 22212, South Korea.
³ Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine Seoul 03080, South Korea.
⁴ Division of Allergy and Clinical Immunology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School Boston, MA 02115, USA.
⁵ College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University Chuncheon 24341, South Korea.
⁶ Department of Pharmacology, Seoul National University College of Medicine Seoul 03080, South Korea.

Abstract

Hypoxia-inducible factors (HIFs) regulate cellular oxygen balance and play a central role in cancer metastasis and angiogenesis. Despite extensive research on HIFs, successful therapeutic strategies remain limited due to the intricate nature of their regulation. In this study, we identified SPATA20, a relatively understudied protein with a thioredoxin-like domain, as an upstream regulator of HIF-1α. Depleting SPATA20 induced HIF-1α expression, suggesting a tumor-suppressive role for SPATA20 in cancer cells. SPATA20 depletion increased HIF-1α protein levels and transcriptional activity without affecting its degradation. It appears that SPATA20 inhibits the de novo synthesis of HIF-1α, possibly by repressing the cap-dependent translation process involving AKT phosphorylation. Additionally, depletion of SPATA20 promoted cancer cell migration and invasion, which can be reversed by pharmacological inhibition of HIF-1α. Clinical data analysis revealed an inverse correlation between SPATA20 expression and colorectal cancer progression, providing evidence of its role as a potential biomarker. Utilizing SPATA20 as an indicator for HIF-1α-targeting therapy may be an attractive strategy for treating patients with hypoxia-driven cancers. In conclusion, this study demonstrates that SPATA20 deficiency promotes cancer progression by activating the HIF-1α signaling pathway.

Keywords: HIF-1α; SPATA20; cancer; hypoxia.