Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100).
Although the precursor protein of NFκB2 (p100) is thought to act as a tumor suppressor in mammalian cells, the molecular mechanism of its anti-tumor activity is far from clear. Here, we are, for the first time, to report that p100 protein expression was dramatically decreased in bladder cancers of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated mice and human patients. Knockdown of p100 in cultured human bladder cancer cells promoted anchorage-independent growth accompanied with elevating abundance of cell-cycle-related proteins and accelerated cell-cycle progression. Above effects could be completely reversed by ectopically expression of p100, but not p52. Mechanistically, p100 inhibited Cyclin D1 protein translation by activating the transcription of LARP7 and its hosted miR-302d, which could directly bind to 3'-UTR of cyclin d1 mRNA and inhibited its protein translation. Furthermore, p100 suppressed the expression of PHLPP2 (PH domain and leucine-rich repeat protein phosphatases 2), thus promoting CREB phosphorylation at Ser133 and subsequently leading to miR-302d transcription. Taken together, our studies not only for the first time establish p100 as a key tumor suppressor of bladder cancer growth, but also identify a novel molecular cascade of PHLPP2/CREB/miR-302d that mediates the tumor suppressive function of p100.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.|Current address: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Jiawei
J
Xu
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Yulei
Y
Wang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Xiaohui
X
Hua
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Jiheng
J
Xu
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Zhongxian
Z
Tian
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Honglei
H
Jin
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Jingxia
J
Li
Department of Urology, New York University School of Medicine, and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USA.
Xue-Ru
XR
Wu
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Chuanshu
C
Huang
D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D014176:Protein Biosynthesis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
D052003:NF-kappa B p52 Subunit; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C541572:PHLPP2 protein, human; C000625223:PHLPP2 protein, mouse; D010749:Phosphoprotein Phosphatases
CREB; NFκB2 (p100); PHLPP2; cyclin D1; miR-302d