LIMD1 Radiosensitizes Human Non-Small Cell Lung Cancer Cells Via Inhibiting NF-kB Signaling

Wu, Zhaojun; Qiu, Minghan; Meng, Maobin; Guo, Yan; Dong, Qian; Yuan, Zhi Yong; Wang, H.; Zeng, Xian

doi:10.1016/j.ijrobp.2015.07.1915

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“…It represses the anti-oncogenic Hippo pathway by antagonizing YAP1 phosphorylation [ 11 , 69 ], and promotes ubiquitination-mediated HIF1α degradation by interacting with the tumor suppressor VHL [ 9 , 10 ]. It is also downregulated, and inhibits NFκB activity and autophagic cell death, in human non-small cell lung cancer cells [ 12 ]. Surprisingly, its expression is positively correlated with expression of the oncogene IRF4 in EBV latency, and it is required for LMP1 oncogenic functions and its depletion promotes DNA damage and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…LIMD1 is involved in the assembly of numerous protein complexes by acting as an adaptor protein that interacts with various proteins such as Rb [ 6 ], TRAF6 [ 7 ], p62/SQSTM1 [ 8 ], VHL and PHD [ 9 , 10 ], and LATS and WW45 [ 11 ], and participates in myriad cellular processes including cell fate determination, cytoskeletal organization, osteoclastogenesis [ 8 ], repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Interaction of LIMD1 with TRAF6 enhances the ability of TRAF6 to activate AP1 and negatively regulates the canonical Wnt receptor signaling pathway in osteoblasts [ 7 ], and interaction with p65 negatively regulates NFκB activity in human non-small cell lung cancer cells [ 12 ]. Our previous study has shown that LIMD1 and IRF4 expression levels positively correlate in different hematological malignancies, including EBV-associated lymphomas [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death

et al. 2017

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LIMD1 (LIM domain-containing protein 1) is considered as a tumor suppressor, being deregulated in many cancers to include hematological malignancies; however, very little is known about the underlying mechanisms of its deregulation and its roles in carcinogenesis. Epstein-Barr Virus (EBV) is associated with a panel of malignancies of lymphocytic and epithelial origin. Using high throughput expression profiling, we have previously identified LIMD1 as a common marker associated with the oncogenic transcription factor IRF4 in EBV-related lymphomas and other hematological malignancies. In this study, we have identified potential conserved IRF4- and NFκB-binding motifs in the LIMD1 gene promoter, and both are demonstrated functional by promoter-reporter assays. We further show that LIMD1 is partially upregulated by EBV latent membrane protein 1 (LMP1) via IRF4 and NFκB in EBV latency. As to its role in the setting of EBV latent infection, we show that LIMD1 interacts with TRAF6, a crucial mediator of LMP1 signal transduction. Importantly, LIMD1 depletion impairs LMP1 signaling and functions, potentiates ionomycin-induced DNA damage and apoptosis, and inhibits p62-mediated selective autophagy. Taken together, these results show that LIMD1 is upregulated in EBV latency and plays an oncogenic role rather than that of a tumor suppressor. Our findings have identified LIMD1 as a novel player in EBV latency and oncogenesis, and open a novel research avenue, in which LIMD1 and p62 play crucial roles in linking DNA damage response (DDR), apoptosis, and autophagy and their potential interplay during viral oncogenesis.

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