Molecular and Cellular Pathobiology Mir-375 Is Activated by Ash1 and Inhibits Yap1 in a Lineage-dependent Manner in Lung Cancer

Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.

[1]  H. Pasolli,et al.  Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin , 2011, Proceedings of the National Academy of Sciences.

[2]  H. Osada,et al.  let‐7 and miR‐17‐92: Small‐sized major players in lung cancer development , 2011, Cancer science.

[3]  C. Croce,et al.  Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells. , 2010, Cancer research.

[4]  Jane J. Sohn,et al.  MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. , 2010, Cancer research.

[5]  M. Brown,et al.  YAP Dysregulation by Phosphorylation or ΔNp63-mediated Gene Repression Promotes Proliferation, Survival and Migration in Head and Neck Cancer Subsets , 2010, Oncogene.

[6]  Emmette R. Hutchison,et al.  miR-375 Inhibits Differentiation of Neurites by Lowering HuD Levels , 2010, Molecular and Cellular Biology.

[7]  Alexander Pertsemlidis,et al.  MicroRNA expression distinguishes SCLC from NSCLC lung tumor cells and suggests a possible pathological relationship between SCLCs and NSCLCs , 2010, Journal of experimental & clinical cancer research : CR.

[8]  Jianmin Si,et al.  MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2 , 2010, Cell Research.

[9]  Li Li,et al.  The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. , 2010, Genes & development.

[10]  Angela M. Liu,et al.  MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. , 2010, Biochemical and biophysical research communications.

[11]  M. Seto,et al.  MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. , 2010, Cancer research.

[12]  N. Baroukh,et al.  Function of microRNA‐375 and microRNA‐124a in pancreas and brain , 2009, The FEBS journal.

[13]  M. Sudol,et al.  Nuclear localization and pro‐apoptotic signaling of YAP2 require intact PDZ‐binding motif , 2009, Genes to cells : devoted to molecular & cellular mechanisms.

[14]  Eran Hornstein,et al.  The Promoter of the pri-miR-375 Gene Directs Expression Selectively to the Endocrine Pancreas , 2009, PloS one.

[15]  M. Sudol,et al.  YAP: At the crossroad between transformation and tumor suppression , 2009, Cell cycle.

[16]  P. Pandolfi,et al.  PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. , 2008, Molecular cell.

[17]  M. Sudol,et al.  Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)* , 2008, Journal of Biological Chemistry.

[18]  C. Mein,et al.  Yes-associated protein (YAP) functions as a tumor suppressor in breast , 2008, Cell Death and Differentiation.

[19]  Y. Yatabe,et al.  Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. , 2008, Cancer research.

[20]  Takuji Yamada,et al.  Association of microRNA‐34a overexpression with proliferation is cell type‐dependent , 2007, Cancer science.

[21]  K. Kaestner,et al.  Characterization of Pancreatic Transcription Factor Pdx-1 Binding Sites Using Promoter Microarray and Serial Analysis of Chromatin Occupancy* , 2007, Journal of Biological Chemistry.

[22]  T Takahashi,et al.  Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92 , 2007, Oncogene.

[23]  Stephen W. Wilson,et al.  MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system , 2007, Genome Biology.

[24]  R. Linnoila.  Functional facets of the pulmonary neuroendocrine system , 2006, Laboratory Investigation.

[25]  Y. Yatabe,et al.  ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. , 2005, Cancer research.

[26]  Y. Yatabe,et al.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. , 2005, Cancer research.

[27]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[28]  L. Castagnoli,et al.  Physical interaction with Yes-associated protein enhances p73 transcriptional activity. , 2001, The Journal of biological chemistry.

[29]  H. Osada,et al.  MicroRNAs in biological processes and carcinogenesis. , 2007, Carcinogenesis.