PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

Abstract

Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon-b (IFNb) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFNb induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2.

A Small Organic Molecule Blocks EGFR Transport into the Nucleus by the Nonclassical Pathway Resulting in Repression of Cancer Invasion

“…It has been reported that nEGFR is involved in regulating MMP2 promotera ctivity. [29] We found that 1 resulted in significant downregulationo f MMP2 expression ands ignificantly suppressed invasion in H1299c ells. NuclearE GFR has also been shown to regulate the proteins that cause tumor invasion, such as cyclin D1 and iNOS.…”

“…EGFR contentsa lso decreased in the nucleus after KPNB1 knockdown to levels similar to those observed after using 100 nm 1;t his is consistent with our findings from confocal microscopy.T ogether,t hese data show that 1 significantly inhibits KPNB1-mediated nucleari mport of EGFR in H1299 cells. It has been reported that nuclear EGFR binds to AT-rich sequence (ATR) in the promoter of matrix metalloprotease-2 (MMP2), [29] which is important for cancerm etastasis, [30] resultingi nt he expression of MMP2.B ecause 1 inhibits the translocation of EGFR to the nucleus, the regulation of MMP2 and the influenceo fM MP2 on invasion by 1 were examined by meanso ft he quantitative reverse-transcription polymerase chain reaction (qRT-PCR). As shown in Figure 3A,t reatment with 20 nm 1 resulted in significantly lower levels of MMP2 expression compared with that of the control value.…”

Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment

“…The antibody against mouse WDR4 was described previously (39). Other antibodies used in this study are the expression of MMP2 and integrin β1 in certain cell types (10,49), their expression was not significantly induced by the WDR4/ PML axis in our cell system. Instead, our study suggests that the WDR4/PML axis acts through uPAR and SAA2 to influence the activity of integrin and MMPs.…”

Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases

“…Interestingly, members of the RTK sub‐families are also present in the nucleus, and are referred to as ‘membrane receptor in the nucleus' or MRINs . Accumulating evidence indicates that at least 12 RTK families contain MRINs that exist either as a holoreceptor or in a truncated form with novel non‐canonical functions in transcriptional regulation, DNA damage and repair, and cell proliferation and invasion . In various cancer types, nuclear RTK expression is associated with poor prognosis .…”