Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Abstract

Background: Considering the increase in the proportion of lung adenocarcinoma (LUAD) cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide, we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.

Methods: The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) data were combined, and a promising risk biomarker called meiotic nuclear divisions 1 (MND1) was selectively acquired. Cell viability assays and subcutaneous xenograft models were used to validate the oncogenic role of MND1 in LUAD cell proliferation and tumor growth. A series of assays, including mass spectrometry, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP), were performed to explore the underlying mechanism.

Results: MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis. In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle. The results of the Co-IP, ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6 (KLF6), and thereby protecting E2F transcription factor 1 (E2F1) from KLF6-induced transcriptional repression. Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.

Conclusions: MND1, KLF6, and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD. MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.

Keywords: E2F transcription factor 1 (E2F1); Kruppel-like factor 6 (KLF6); cell cycle; cisplatin resistance; lung adenocarcinoma; meiotic nuclear divisions 1 (MND1); positive feedback loop.