TdIF1-LSD1 Axis Regulates Epithelial-Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Demethylation* ; Promoter Regions, Genetic*; Cadherins/*genetics ; DNA-Binding Proteins/*metabolism ; Epithelial-Mesenchymal Transition/*genetics ; Histone Demethylases/*metabolism ; Histones/*metabolism ; Lung Neoplasms/*genetics ; Transcription Factors/*metabolism; Animals ; Cadherins/metabolism ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Down-Regulation/genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Lung Neoplasms/pathology ; Lysine/metabolism ; Methylation ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Protein Binding ; Mice

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial-mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.

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Keywords: EMT; LSD1; NSCLC; TdIF1

0 (Cadherins)
0 (DNA-Binding Proteins)
0 (DNTTIP1 protein, human)
0 (Histones)
0 (Transcription Factors)
EC 1.14.11.- (Histone Demethylases)
EC 1.5.- (KDM1A protein, human)
K3Z4F929H6 (Lysine)

Date Created: 20220111 Date Completed: 20220201 Latest Revision: 20240226

20240226

PMC8745707

10.3390/ijms23010250

35008676