Journal
MOLECULAR THERAPY
Volume 29, Issue 6, Pages 2121-2133Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2021.02.014
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Funding
- National Key Research and Development Plan [2018YFC1106100]
- National Natural Science Foundation of China [81772875, 81872339, 81802702]
- China Postdoctoral Science Foundation [2020M681328]
- Science and Technology Commission of Shanghai [17DZ2260100, 19JC1410200]
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The study revealed that upregulation of BACE2 in ocular melanoma significantly impairs tumor progression, and its inhibition may lead to exhaustion of intracellular calcium release. TMEM38B, highly dependent on BACE2, modulates calcium release from the endoplasmic reticulum.
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 N-6-methyladenosine (m(6)A) 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 m(6)A/BACE2/TMEM38b could be a potential therapeutic axis for ocular melanoma.
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