Promoter methylation of TCF21 may repress autophagy in the progression of lung cancer
- 233 Downloads
Lung cancer is a leading cause of cancer mortality worldwide. Promoter methylation of transcription factor 21 (TCF21) was frequently observed in the early stage of non-small cell lung cancer (NSCLC). However, clinical relevance and molecular functions of TCF21 in NSCLC progression remain unclear. In this study, we analyzed the associations between TCF21 expression and clinicopathological features in 100 patients with NSCLC and revealed the underlying molecular mechanisms of TCF21 methylation on cell viability, apoptosis and invasion of H1299 cells. We found that the expression of TCF21 was significantly regulated by its methylation level in patients with NSCLC and was associated with tumor stage, metastasis and invasion. Demethylation of H1299 cells by 5-aza-2′-deoxycytine (5-Aza) demonstrated that a higher level of TCF21 expression led to remarkable decreases of cell viability and invasion ability but an increase of cell apoptosis. Accordingly, TCF21 knockdown showed converse results to high expression of TCF21. TCF21 knockdown cells exhibited significantly upregulated ATG-9, BECLIN-1, and LC3-I/II expressions but decreased p62 expression compared to wildtype cells. Inhibition of autophagy by 3-methyladenine (3-MA) elevated TCF21 expression and increased cell apoptosis. TCF21 expression is clinically related to the progress of lung cancer and may inhibit autophagy by suppressing ATG-9 and BECLIN-1. In turn, autophagy may also play an important role in regulation TCF21 expression.
KeywordsTranscription factor 21 (TCF21) Methylation Non-small cell lung cancer (NSCLC) Autophagy
transcription factor 21
non-small cell lung cancer
This study was funded by the Science and Technology Development Fund Project of Shenzhen (No. JCYJ 20150403091443278 and JCYJ 20150403091443310).
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to disclose.
- Arab K, Smith LT, Gast A, Weichenhan D, Huang JP, Claus R, Hielscher T, Espinosa AV, Ringel MD, Morrison CD, Schadendorf D, Kumar R, Plass C (2011) Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma. Carcinogenesis 32:1467–1473CrossRefPubMedPubMedCentralGoogle Scholar
- Ferlay J, Bray F, Pisani P, Parkin D (2004) Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No. 5, version 2.0. IARCPress, LyonGoogle Scholar
- Howlader N, Noone A, Krapcho M, Garshell J, Miller D, Altekruse S, Kosary C, Yu M, Ruhl J, Tatalovich Z (2015) SEER cancer statistics review, 1975–2012. National Cancer Institute, BethesdaGoogle Scholar
- Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu X-C, Eheman C, Anderson R (2008) Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100:1672–1694CrossRefPubMedPubMedCentralGoogle Scholar
- Nurnberg ST, Cheng K, Raiesdana A, Kundu R, Miller CL, Kim JB, Arora K, Carcamo-Oribe I, Xiong Y, Tellakula N (2015) Coronary artery disease associated transcription factor TCF21 regulates smooth muscle precursor cells that contribute to the fibrous cap. PLoS Genet 11:e1005155CrossRefPubMedPubMedCentralGoogle Scholar