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

Qi Liu,Yujuan Zhang,Zhigang Wang,Nan Hao,Jacques Raphael,Juan Xiong,Yi Sang,Derong Xu,Hong Diao,Weiping Min,Saman Maleki Vareki,Jeffrey Min,Xiufen Zheng,James Koropatnick

doi:10.3390/ijms23010250

Abstract

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.

Highlights

Lung cancer is the most common malignant cancer and the leading cause of cancerrelated deaths in both men and women worldwide [1]
TdT-interacting factor 1 (TdIF1) Is Highly Expressed in non-small cell lung cancer (NSCLC) and Positively Correlated with Metastasis
We investigated whether TdIF1 can bind to the E-cadherin promoter region using chromatin immunoprecipitation (ChIP) analysis

Summary

Introduction

Lung cancer is the most common malignant cancer and the leading cause of cancerrelated deaths in both men and women worldwide [1]. Comprises more than 80% of all lung cancer cases, and its main subtypes include lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) [2,3]. Treatments for NSCLC include surgical resection, radiotherapy, chemotherapy, immunotherapy, and targeted therapies. Relevant treatment research has made significant progress in recent years, the five-year overall survival rate of NSCLC patients remains less than 20% [4]. Various factors affect NSCLC development, progression, and patient outcome, including mutation, metastasis, and drug resistance [5,6,7]. We do not yet have a complete understanding of the mechanism. Further studies of NSCLC-related molecular mechanisms are essential to improve treatments and the survival rates of NSCLC patients

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Conclusion