Oxidative stress activates NORAD expression by H3K27ac and promotes oxaliplatin resistance in gastric cancer by enhancing autophagy flux via targeting the miR-433-3p

Abstract

Oxaliplatin resistance undermines its curative effects on cancer and usually leads to local recurrence. The oxidative stress induced DNA damage repair response is an important mechanism for inducing oxaliplatin resistance by activating autophagy. ELISA is used to detect target genes expression. TMT-based quantitative proteomic analysis was used to investigate the potential mechanisms involved in NORAD interactions based on GO analysis. Transwell assays and apoptosis flow cytometry were used for biological function analysis. CCK-8 was used to calculate IC50 and resistance index (RI) values. Dual-luciferase reporter gene assay, RIP and ChIP assays, and RNA pull-down were used to detect the interaction. Autophagy flux was evaluated using electron microscope and western blotting. Oxidative stress was enhanced by oxaliplatin; and oxaliplatin resistance gastric cancer cell showed lower oxidative stress. TMT labeling showed that NORAD may regulate autophagy flux. NORAD was highly expressed in oxaliplatin-resistant tissues. In vitro experiments indicate that NORAD knockdown decreases the RI (Resistance Index). Oxaliplatin induces oxidative stress and upregulates the expression of NORAD. SGC-7901 shows enhanced oxidative stress than oxaliplatin-resistant cells (SGC-7901-R). NORAD, activated by H3K27ac and CREBBP, enhanced the autophagy flux in SGC-7901-R to suppress the oxidative stress. NORAD binds to miR-433-3p and thereby stabilize the ATG5- ATG12 complex. Our findings illustrate that NORAD, activated by the oxidative stress, can positively regulate ATG5 and ATG12 and enhance the autophagy flux by sponging miR-433-3p. NORAD may be a potential biomarker for predicting oxaliplatin resistance and mediating oxidative stress, and provides therapeutic targets for reversing oxaliplatin resistance.

Tanshinone IIA inhibits gastric cancer cell stemness through inducing ferroptosis

“…On account of that Tanshinone IIA is able to increase the sensitivity of various drug‐resistant gastric cancer cells to first‐line chemotherapeutic drugs, 28,34 we hypothesized that Tanshinone IIA could improve chemotherapy resistance through reducing tumor stemness, which is directly related to chemo‐resistance 35 . BGC‐823 and SGC‐7901 were used as gastric adenocarcinoma models because many researches have showed that BGC‐823 cells and SGC‐7901 cells represent undifferentiated and moderately differentiated gastric cancer cells, respectively 36–39 . There have been some researches about Tanshinone IIA which plays an important role in inhibiting tumor stem cells.…”

BMSC-EV-derived lncRNA NORAD Facilitates Migration, Invasion, and Angiogenesis in Osteosarcoma Cells by Regulating CREBBP via Delivery of miR-877-3p

“…After silencing NORAD, miR-877-3p was upregulated and CREBBP was downregulated in OS cells treated with EVs. The binding relationship between CREBBP and NORAD has been identified earlier [ 33 ]. Similarly, the current study ascertained that NORAD carried by BMSC-EVs promoted CREBBP expression by sponging miR-877-3p.…”

Chk1 Inhibition Hinders the Restoration of H3.1K56 and H3.3K56 Acetylation and Reprograms Gene Transcription After DNA Damage Repair

“…It has been reported that DNA damage triggers a decrease in cellular H3K27ac levels ( 33 ) or induces an enrichment of H3K27ac at specific promoter regions ( 34 ). Accordingly, our data showed that the levels of both H3.1K27ac and H3.3K27ac decreased after UV radiation.…”