Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin.
Menin upregulates transcription of cell-cycle inhibitors to suppress endocrine tumors, but it is poorly understood how menin suppresses non-endocrine tumors such as lung cancer. Here, we show that menin inhibits proliferation of human lung cancer cells and growth of lung cancer in mice. The menin-mediated tumor suppression requires repression of growth factor pleiotrophin (PTN), which binds to its cell surface receptor, anaplastic lymphoma kinase (ALK) that is activated in certain lung adenocarcinomas. Menin represses PTN transcription and PTN-induced proliferation of human lung cancer cells, and menin expression is substantially reduced in primary human lung adenocarcinomas. Notably, menin binds the PTN locus and enhances Polycomb gene Enhancer of Zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27m3), a negative mark for gene transcription but does not affect histone H3K4 methylation that is usually upregulated by menin in endocrine cells. Together, our findings indicate that menin suppresses lung cancer partly through increasing Polycomb gene-mediated H3K27 methylation and repressing PTN transcription, unraveling a novel, epigenetically regulated PTN-ALK signaling pathway in suppressing lung cancer.
Gao
S-B
SB
Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361005, Fujian, PR China.
Feng
Z-J
ZJ
Xu
B
B
Wu
Y
Y
Yin
P
P
Yang
Y
Y
Hua
X
X
Jin
G-H
GH
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D063151:Polycomb Repressive Complex 2; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D016207:Cytokines; D006657:Histones; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C066845:pleiotrophin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases