CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma.
Sivasundaram KarnanAkinobu OtaHideki MurakamiMd Lutfur RahmanMd WahiduzzamanMuhammad Nazmul HasanLam Quang VuIchiro HanamuraAkihito InokoMiho RikuHideaki ItoYoshifumi KanekoToshinori HyodoHiroyuki KonishiShinobu TsuzukiYoshitaka HosokawaPublished in: Cell death discovery (2023)
Malignant mesothelioma (MMe) is a rare but aggressive malignancy. Although the molecular genetics of MMe is known, including BRCA1-associated protein-1 (BAP1) gene alterations, the prognosis of MMe patients remains poor. Here, we generated BAP1 knockout (BAP1-KO) human mesothelial cell clones to develop molecular-targeted therapeutics based on genetic alterations in MMe. cDNA microarray and quantitative RT-PCR (qRT-PCR) analyses revealed high expression of a calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D) gene in the BAP1-KO cells. CAMK2D was highly expressed in 70% of the human MMe tissues (56/80) and correlated with the loss of BAP1 expression, making it a potential diagnostic and therapeutic target for BAP1-deficient MMe. We screened an anticancer drugs library using BAP1-KO cells and successfully identified a CaMKII inhibitor, KN-93, which displayed a more potent and selective antiproliferative effect against BAP1-deficient cells than cisplatin or pemetrexed. KN-93 significantly suppressed the tumor growth in mice xenografted with BAP1-deficient MMe cells. This study is the first to provide a potential molecular-targeted therapeutic approach for BAP1-deficient MMe.
Keyphrases
- induced apoptosis
- cell cycle arrest
- endothelial cells
- protein kinase
- poor prognosis
- endoplasmic reticulum stress
- genome wide
- single cell
- small molecule
- dna methylation
- copy number
- signaling pathway
- high resolution
- climate change
- type diabetes
- binding protein
- wild type
- metabolic syndrome
- pi k akt
- mass spectrometry
- long non coding rna
- human health
- risk assessment
- real time pcr