Abstract
Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.
Highlights
Cancer ranks as a leading cause of death and an important barrier to extend life expectancy in every country of the world
The regulation and relevance of Post-translational modification (PTM) of lysine-specific demethylase 5B (KDM5B) under hypoxia remain largely undefined. We found another small ubiquitin-related modifier (SUMO) E3 ligase protein inhibitor of activated STAT 4 (PIAS4) mediated KDM5B SUMOylation under hypoxia to protect it from ubiquitination-dependent proteasomal degradation, which was important for the hypoxia adaption of gastric cancer (GC) cells
To investigate the involvement of KDM5B in GC, we examined KDM5B expression by immunohistochemical staining in tissue microarrays (TMAs) containing collected tumor tissue samples and the matched normal adjacent tissues from 71 GC patients
Summary
Cancer ranks as a leading cause of death and an important barrier to extend life expectancy in every country of the world. Hypoxia is a state of low oxygen tension which is common in numerous solid tumors typically associated with abnormal vasculature (Sharma et al, 2019). Tumor cells have to undergo adaptive genetic or epigenetic changes resulting into metabolic remodeling, angiogenesis, or invasiveness to overcome multiple hypoxia-associated challenges (Patel and Sant, 2016). Tumor cells adapted to hypoxia have a growth advantage and become resistant to chemotherapy or radiotherapy, conferring worse prognosis (Hammond and Giaccia, 2006). Co-targeting hypoxia adaption would be essential to improve such antiangiogenesis therapies
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