Downregulation of CISD2 Has Prognostic Value in Non-Small Cell Lung Cancer and Inhibits the Tumorigenesis by Inducing Mitochondrial Dysfunction

Abstract

CISD2, a NEET protein that coordinates 2Fe-2S clusters through its CDGSH domain, is critical for normal development and iron homeostasis. CISD2 plays an important role in Fe-S cluster transfer and promotes cancer proliferation. However, its specific role in the development of non-small cell lung cancer (NSCLC) remains unclear. Bioinformatics of pan-cancer analysis from The Cancer Genome Atlas show that CISD2 has an aberrant expression in most types of human cancers. Moreover, CISD2 expression is associated with a higher hazard ratio and exhibits significantly poorer overall survival in lung adenocarcinoma (LUAD), uveal melanoma, head and neck squamous cell carcinoma, brain lower grade glioma, kidney chromophobe, and liver hepatocellular carcinoma. Further investigation revealed that CISD2 is highly expressed in LUAD and LUSC, which is associated with clinical pathological stages. In addition, survival data collected from GSE31210 and GSE13213, two datasets from the NCBI Gene Expression Omnibus, also confirmed that high CISD2 expression is associated with unfavorable survival in patients with LUAD. A cell-based assay indicated that the knockdown of CISD2 inhibited proliferation, invasion, and migration in A549 cells. Additionally, CISD2 knockdown accelerated the accumulation of cellular and mitochondrial reactive oxygen species, destroying the mitochondrial morphology and function. Moreover, CISD2 inhibition activated the iron starvation response, thus, accelerating iron accumulation in A549 cells. Pretreatment with DFO, the iron chelator, blocked mitochondrial dysfunction in CISD2-knockdown cells. Collectively, the present study provides novel insights into the regulatory role of CISD2 in NSCLC and presents a potential target to improve antitumor activity based on oxidative stress.

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

“…1; [27]) is driving the accumulation of iron in aging cardiomyocytes and that this process is accompanied by elevated expression of TfR (that subsides by 55 weeks of age). In contrast, the absence of CISD2 in cardiomyocytes from young mice could drive an active process of iron uptake, similar to the processes observed in different cells upon iron starvation, or in cancer cells that actively accumulate iron [16,17,37,52,57,58]. Because we did not analyze the expression of TfR and ferritins in cardiomyocytes during different stages of the aging process, we cannot determine whether the mechanisms of iron accumulation found in cardiomyocytes from old and young CISD2‐ KO mice are similar.…”

“…Previous studies revealed that different cell types with reduced CISD2 or CISD1 expression accumulate high levels of iron in their mitochondria and display enhanced expression of TfR and ferritin [54,58,63]. This process is also accompanied by the activation of apoptosis, autophagy, and ferroptosis [16,33,50,54,57,58,64,65].…”

“…Previous studies revealed that different cell types with reduced CISD2 or CISD1 expression accumulate high levels of iron in their mitochondria and display enhanced expression of TfR and ferritin [54,58,63]. This process is also accompanied by the activation of apoptosis, autophagy, and ferroptosis [16,33,50,54,57,58,64,65]. The similarities observed between cells with suppressed CISD2 or CISD1 expression led to the hypothesis that these two proteins participate in similar or overlapping processes [16,32,54].…”

High Expression of CISD2 in Relation to Adverse Outcome and Abnormal Immune Cell Infiltration in Glioma

“…In hepatocellular carcinoma, the expression of CISD2 is associated with advanced clinicopathological characteristics, such as tumor size, number of tumors, surgical margin, recurrence, and poor prognosis [ 13 ]. Shao et al [ 41 ] revealed that CISD2 could be developed as a chemotherapeutic target in human breast cancer owing to its effect on cell proliferation. And Sun et al [ 14 ] reported that CISD2 was significantly increased in glioma tissues and could promote cell proliferation by inhibiting beclin-1-mediated autophagy.…”

CISD3 inhibition drives cystine-deprivation induced ferroptosis

“…In recent years, several iron−sulfur proteins have been identified associated with ferroptosis [ 23 , 24 ]. Other studies also found that MitoNEET and NAF-1 play a vital role in the pathology of obesity, diabetes, heart disease, neurodegeneration, and cancer progression [ 17 , 25 , 26 ]. Limited information has been published on the homologous protein CISD3, which harbors one [2Fe−2S] cluster within a single polypeptide chain.…”