Dataset Information

M⁶A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

ABSTRACT: Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common and deadly eye cancer in adults. Both UM and CM originate from melanocytes and exhibit an aggressive growth pattern with high rates of metastasis and mortality. The integral membrane glycoprotein beta-secretase 2 (BACE2), an enzyme that cleaves amyloid precursor protein into amyloid beta peptide, has been reported to play a vital role in vertebrate pigmentation and metastatic melanoma. However, the role of BACE2 in ocular melanoma remains unclear. In this study, we showed that BACE2 was significantly upregulated in ocular melanoma, and inhibition of BACE2 significantly impaired tumor progression both in vitro and in vivo. Notably, we identified that transmembrane protein 38B (TMEM38B), whose expression was highly dependent on BACE2, modulated calcium release from endoplasmic reticulum (ER). Inhibition of the BACE2/TMEM38B axis could trigger exhaustion of intracellular calcium release and inhibit tumor progression. We further demonstrated that BACE2 presented an increased level of N⁶-methyladenosine (m⁶A) RNA methylation, which led to the upregulation of BACE2 mRNA. To our knowledge, this study provides a novel pattern of BACE2-mediated intracellular calcium release in ocular melanoma progression, and our findings suggest that m⁶A/BACE2/TMEM38b could be a potential therapeutic axis for ocular melanoma.

SUBMITTER: He F

PROVIDER: S-EPMC8178445 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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m<sup>6</sup>A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

He Fanglin F Yu Jie J Yang Jie J Wang Shaoyun S Zhuang Ai A Shi Hanhan H Gu Xiang X Xu Xiaofang X Chai Peiwei P Jia Renbing R

Molecular therapy : the journal of the American Society of Gene Therapy 20210215 6

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common and deadly eye cancer in adults. Both UM and CM originate from melanocytes and exhibit an aggressive growth pattern with high rates of metastasis and mortality. The integral membrane glycoprotein beta-secretase 2 (BACE2), an enzyme that cleaves amyloid precursor protein into amyloid beta peptide, has been reported to play a vital role in vertebrate pigmentation and metastatic melanoma. However, the ...[more]

PMID: 33601055

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Project description:The nutritional status of dairy cows and the metabolism of specific nutrients are critical regulators of immune cell function. Around the time of parturition, mobilization of body lipid and muscle helps compensate for the decrease in nutrient intake and the increased requirements of the mammary gland for lactation. An end-result of these processes is the marked increase in circulating concentrations of fatty acids (FA), which are a major risk factor for immune dysfunction. In food animal species such as dairy cows, any disturbance in nutritional or immunological homeostasis leads to deleterious feedback loops that can further risk health, efficiency of nutrient use, and compromise availability of safe and nutritious dairy foods for humans. Despite substantial progress with respect to regulation of innate immunity, such knowledge for adaptive immunity is scarce. To help bridge this gap in knowledge, we sought to study the role of calcium release-activated calcium modulator ORAI1 activation in T cells systemic immune function in vivo. CD4+ T cells were isolated from peripheral blood of dairy cows diagnosed as healthy or with ketosis, a common metabolic disorder of FA metabolism. Results revealed that levels of intracellular Ca2+ and reactive oxygen species (ROS) along with the abundance of store-operated Ca2+ entry (SOCE) moiety increased during ketosis. Further, plasma concentrations of inflammatory cytokines were elevated, the balance of Th17/Treg cells was disrupted, mitochondrial function impaired, and the abundance of mitophagy-related proteins in CD4+ T cells altered during ketosis. Molecular characterization of the direct effects of FA was evaluated in CD4+ T cells isolated from the spleen of 1-day-old calves. Enhanced supply of FA increased intracellular Ca2+ and ROS concentrations, upregulated the abundance of proteins associated with mitochondrial dynamics and ORAI1. Intermediates of mitophagy accumulated and the balance of Th17/Treg cells also was affected by the supply of FA. These negative effects were attenuated by silencing or inhibition of ORAI1 in CD4+ T cells. Together, data indicated that physiological states that lead to increases in systemic concentrations of FA could impact adaptive immunity negatively through ORAI1 regulated intracellular Ca2+, ROS balance, and increased effector functions of Th17 cells.

Dataset Information

M⁶A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

Publications

m<sup>6</sup>A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

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Dataset Information

M6A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

Publications

m<sup>6</sup>A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

M⁶A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma.