The PML isoform IV is a negative regulator of nuclear EGFR’s transcriptional activity in lung cancer

Abstract

Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase, which can transduce intracellular signals responsible for cell proliferation. It is frequently overexpressed and/or constitutively activated in non-small cell lung cancer and thus is considered as a major cause of this disease. Recently, EGFR has been found in the nucleus where the nuclear EGFR (nEGFR) can function as a transcription factor activating the transcription of genes such as cyclin D1 gene (CCND1), which is essential for cell proliferation. Nevertheless, how nEGFR's transcriptional activity is regulated remains unclear. Promyelocytic leukemia protein (PML) is a tumor suppressor, which is lost in various cancers including lung cancer. However, the role of PML in the suppression of lung cancer growth is still unclear. When we investigated the role of PML in the regulation of lung cancer cell growth, we found that PML isoform IV (PMLIV) preferentially represses the growth of lung cancer cells bearing constitutively active EGFR. Besides, when growing in the EGFR activating conditions, the growth of EGFR wild-type bearing A549 cells has been repressed by PMLIV overexpression. We also found that PMLIV can interact physically with nEGFR and represses the transcription of nEGFR target genes. We showed that PMLIV is recruited by nEGFR to the target promoters and reduces the promoter histone acetylation level via HDAC1. Together, our results suggest that PMLIV interacts with nEGFR upon EGFR activation and represses the transcription of nEGFR target genes such as CCND1 and thus leading to inhibition of the lung cancer cell growth.

Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis

“…Notably, a specific PML isoform with a molecular mass of 95 kDa interacted with Pin1 and corresponded to the most extensively studied isoform ( Figure 7A). 19,20 Consistent with our co-IP results, PML and Pin1 were found co-localized under confocal microscopy in cultured NMCFs. Pin1 exhibited a diffuse distribution throughout the nucleus and a partial colocalization with PML (Figure 7B).…”

Microtubule-Associated Protein 1 Light Chain 3 Interacts with and Contributes to Growth Inhibiting Effect of PML

“…As shown in Figure 8a, Flag tagged WT and DM PML demonstrated similar protein expression levels. Consistent with previous report [36], WT PML-expressing cells depicted a significant growth inhibition compared with that of vector expressing cells, as assessed by CCK-8 assay. Intriguingly, we found that DM PML expressing cells completely lost this growth inhibition effect (Figure 8b), suggesting that association of PML with LC3 may facilitate PML-conducted growth inhibition.…”

Towards Engineering Novel PE-Based Immunotoxins by Targeting Them to the Nucleus

“…However, lack of nuclear transport of proteins containing NLS sequence in this cell line has already been presented [41]. Similar to our observations, EGFR containing a tripartite NLS (RRRHIVRKRTLRR) was detected in nucleus of HCC827 cells but was barely detectable in nuclear compartment of A549 cells [42,43]. These findings suggest that importins-dependent route in A549 is not efficient as compared to other cell lines.…”