MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.

Autor:	Llabata P; Cancer Genetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain., Torres-Diz M; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08908 Barcelona, Spain., Gomez A; Rheumatology Research Group, Vall d'Hebron Research Institute, 08035 Barcelona, Spain., Tomas-Daza L; 3D Chromatin Organization Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain., Romero OA; Cancer Genetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain., Grego-Bessa J; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08908 Barcelona, Spain., Llinas-Arias P; Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain., Valencia A; Computational Biology Life Sciences Group, Barcelona Supercomputing Centre, 08034 Barcelona, Spain., Esteller M; Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer, 28029 Madrid, Spain.; Institucio Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, 08907 Barcelona, Spain., Javierre BM; Rheumatology Research Group, Vall d'Hebron Research Institute, 08035 Barcelona, Spain., Zhang X; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112., Sanchez-Cespedes M; Cancer Genetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain; mscespedes@carrerasresearch.org.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Sep 14; Vol. 118 (37).
DOI:	10.1073/pnas.2024824118
Abstrakt:	The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu