FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis

Abstract

Background FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC). Methods Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay. Findings Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan–Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca 2+ cytosol influx from ER and extracellular, as well as NFATC1 nuclear translocation and activity. Nuclear NFATC1 bound to the BMI1 gene promoter and transcriptionally upregulated its expression. Notably, BMI1 overexpression could rescue the loss of function of FUNDC1. Co-expression of FUNDC1 and BMI1 in BC patients predicted worse prognosis than without either expression. Interpretation FUNDC1 might promote BC progression by activating the Ca 2+ –NFATC1–BMI1 axis. This pathway may be promising for developing multiple targets for BC therapy.

Prognostic and Immunological Role of FUN14 Domain Containing 1 in Pan-Cancer: Friend or Foe?

“…It is now acknowledged that mitophagy is closely related to human immunity. Moreover, to the best of our knowledge, the relationship between FUNDC1 expression and tumor cell proliferation has been proved in cervical and breast cancers (6,29). Thus, it is reasonable to surmise that FUNDC1 expression may influence patient survival through tumor cell proliferation.…”

“…FUNDC1 interacts with molecules like LC3B, which is found on the mitochondria-associated membrane of the endoplasmic reticulum, to maintain good mitochondrial quality by forming mitophagosomes (4). FUNDC1related mitochondrial dysfunction contributes to various pathophysiological processes, such as heart diseases, metabolic disorders, and cancers (6)(7)(8)(9). In cardiovascular and metabolic diseases, FUNDC1 is generally considered to be protective because FUNDC1-mediated mitophagy can alleviate damage caused by intracellular stress such as hypoxia and thus benefit overall outcomes (9,10).…”

“…Meanwhile, the role of FUNDC1 might be context dependent and could vary among different cancers. For example, FUNDC1 can promote tumor progression and predict poor prognosis in some cancer types; however, it can also suppress carcinogenesis through mitophagy (6,7,11). Thus, it remains unclear whether FUNDC1 can be characterized as a friend or foe in pan-cancer.…”

Mitophagy in Acute Kidney Injury and Kidney Repair

“…Notably, FUNDC1 can also regulate mitochondrial dynamics via interacting with DRP1 or OPA1 (OPA1 mitochondrial dynamin-like GTPase), respectively. FUNDC1 phosphorylation at Ser13 facilitates its interaction with OPA1 to inhibit mitochondrial fission, whereas FUNDC1 dephosphorylation at Ser13 releases FUNDC1 from OPA1 and promotes its interaction with DRP1 to induce mitochondrial fission and mitophagy under cell stress [84,85].…”

LKB1 Loss Upregulates ALKBH5 and Contributes to Aggressive Phenotypes of KRAS Mutated Lung Cancer

“…We performed IHC analysis of para n-embedded lung cancer tissues containing primary tumors and matched normal lung tissues as previously described [24,25]. In brief, we de-para nized and rehydrated human tissue sections to retrieve antigens by microwaving the sections in 10 mM Sodium Citrate (pH 6.0), and then incubating in 1% hydrogen peroxide to suppress endogenous peroxidase activity.…”