A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers

Vrba, Lukas; Garbe, James C.; Stampfer, Martha R.; Futscher, Bernard W.

doi:10.1080/15592294.2015.1106673

Title: A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers

Journal Article · Mon Oct 19 00:00:00 EDT 2015 · Epigenetics

DOI:https://doi.org/10.1080/15592294.2015.1106673· OSTI ID:1257370

Vrba, Lukas ^[1]; Garbe, James C. ^[2]; Stampfer, Martha R. ^[3]; Futscher, Bernard W. ^[1]

Univ. of Arizona, Tucson, AZ (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Univ. of Arizona, Tucson, AZ (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Immortality is an essential characteristic of human carcinoma cells. We recently developed an efficient, reproducible method that immortalizes human mammary epithelial cells (HMEC) in the absence of gross genomic changes by targeting 2 critical senescence barriers. Consistent transcriptomic changes associated with immortality were identified using microarray analysis of isogenic normal finite pre-stasis, abnormal finite post-stasis, and immortal HMECs from 4 individuals. A total of 277 genes consistently changed in cells that transitioned from post-stasis to immortal. Gene ontology analysis of affected genes revealed biological processes significantly altered in the immortalization process. These immortalization-associated changes showed striking similarity to the gene expression changes seen in The Cancer Genome Atlas (TCGA) clinical breast cancer data. The most dramatic change in gene expression seen during the immortalization step was the downregulation of an unnamed, incompletely annotated transcript that we called MORT, for mortality, since its expression was closely associated with the mortal, finite lifespan phenotype. We show here that MORT (ZNF667-AS1) is expressed in all normal finite lifespan human cells examined to date and is lost in immortalized HMEC. MORT gene silencing at the mortal/immortal boundary was due to DNA hypermethylation of its CpG island promoter. This epigenetic silencing is also seen in human breast cancer cell lines and in a majority of human breast tumor tissues. The functional importance of DNA hypermethylation in MORT gene silencing is supported by the ability of 5-aza-2'-deoxycytidine to reactivate MORT expression. Analysis of TCGA data revealed deregulation of MORT expression due to DNA hypermethylation in 15 out of the 17 most common human cancers. The epigenetic silencing of MORT in a large majority of the common human cancers suggests a potential fundamental role in cellular immortalization during human carcinogenesis.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1257370

Alternate ID(s):: OSTI ID: 1407279

Journal Information:: Epigenetics, Vol. 10, Issue 11; ISSN 1559-2294

Publisher:: Taylor & FrancisCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 24 works

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Related Subjects

60 APPLIED LIFE SCIENCES
breast cancer
DNA methylation
epigenetics
immortality
HMEC
lncRNA
lincRNA
MORT
mammary epithelia
ncRNA
ZNF667-AS1

A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers Vrba, Lukas; Garbe, James C.; Stampfer, Martha R. https://doi.org/10.6084/m9.figshare.2066664 The current record is supplemented by this dataset	dataset	January 2015
A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers Vrba, Lukas; Garbe, James C.; Stampfer, Martha R. https://doi.org/10.6084/m9.figshare.2066664.v1 The current record is supplemented by this dataset	dataset	January 2016
A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers Vrba, Lukas; Garbe, James C.; Stampfer, Martha R. https://doi.org/10.6084/m9.figshare.1621372 The current record is supplemented by this dataset	dataset	January 2015