BAP1 and PTEN prevent IP3R3 degradation, increasing Ca2+ flux and apoptosis to suppress tumor growth.
Major finding: BAP1 and PTEN prevent IP3R3 degradation, increasing Ca2+ flux and apoptosis to suppress tumor growth.
Mechanism: BAP1 deubiquitinates IP3R3 and PTEN competes with FBXL2 for IP3R3 binding to promote IP3R3 stabilization.
Impact: Inhibiting IP3R3 degradation may be a potential therapeutic strategy in BAP1- or PTEN-deficient tumors.
The type 3 inositol-1,4,5-triphosphate receptor (IP3R3) controls calcium (Ca2+) release from the endoplasmic reticulum (ER) to the mitochondria. Persistent Ca2+ release overloads the mitochondria and results in apoptosis. Related studies identified two tumor suppressor proteins, BAP1 and PTEN, that promote IP3R3-mediated Ca2+ flux to promote apoptosis and suppress oncogenic transformation. Bononi and colleagues found that BAP1 binds to and deubiquitinates IP3R3 at the ER, thereby stabilizing IP3R3, enhancing Ca2+ flux, and promoting apoptosis. BAP+/− fibroblasts exhibited reduced IP3R3 protein levels, decreased mitochondrial Ca2+ uptake, and reduced apoptosis compared to wild-type fibroblasts. BAP1 also exhibited nuclear activity, and BAP1 depletion impaired DNA damage repair, resulting in enhanced DNA damage. Although these cells accumulated increased DNA damage, they could not execute apoptosis due to reduced mitochondrial Ca2+. In primary human mesothelial cells, asbestos exposure promoted malignant transformation, which was increased by depletion of IP3R3 or BAP1, although BAP1 depletion had a stronger effect due to its additional nuclear function. Kuchay, Giorgi, and colleagues found that PTEN also prevents IP3R3 degradation. Mechanistically, PTEN competed with FBXL2 for IP3R3 binding, and, as FBXL2 promoted proteasome-mediated degradation of IP3R3, PTEN binding stabilized IP3R3. FBXL2 depletion increased Ca2+ release from the ER and sensitized cells to apoptosis. Conversely, PTEN loss promoted FBXL2-mediated degradation of IP3R3, and PTEN reconstitution, irrespective of its phosphatase activity, stabilized IP3R3 to induce Ca2+ mobilization and apoptosis. Moreover, expression of PTEN and IP3R3 were correlated in human prostate cancer. In prostate cancer xenografts, a nondegradable IP3R3 mutant or an inhibitor that disrupted FBXL2 membrane localization sensitized tumors expressing low levels of PTEN to photodynamic therapy, which induces Ca2+-dependent cytotoxicity. Taken together, these studies elucidate mechanisms by which BAP1 or PTEN stabilize IP3R3 to promote mitochondrial Ca2+ overload and apoptosis, thereby limiting tumor growth. These findings suggest the possibility for drugs that stabilize IP3R3 to treat BAP1- or PTEN-deficient tumors.
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