title: KDM6A is an epigenetic gatekeeper of mTORC1 signaling in cancer
creator: Revia, Steffie
subject: 570
subject: 570 Life sciences
description: Kdm6a is a histone H3K27-specific demethylase and a component of the highly conserved MLL3/4-COMPASS-like complex. Genomic sequencing studies of human tumor samples revealed frequent deletions and/or loss-of-function mutations of Kdm6a in various human cancer types, suggesting an important role in tumorigenesis. Yet, despite its frequent alterations in human cancer, biological functions mediated by Kdm6a during malignant transformation and progression remain poorly understood.   To gain further insights to these questions, we generated mouse models with liver-specific deletion or downregulation of Kdm6a by CRISPR/Cas9 or inducible RNA-interference, respectively. Disruption of Kdm6a by both approaches led to formation of aggressive hepatocellular carcinomas (HCC) in a short time frame. Conversely, endogenous re-expression of Kdm6a in Kdm6a-deficient tumors significantly reduced tumor progression and prolonged survival in vivo.  Transcriptional profiling linked the apparent Kdm6a tumor suppressor activity to regulation of mTOR signaling and epigenetic profiling using Cut&Run analyses revealed control of Deptor and Tsc2, two known negative regulators of mTOR signaling, by Kdm6a. Interestingly, the observed expression changes occurred in the absence of changes in H3K27me3 deposition. Immediate biochemical validation reaffirmed aberrant up-regulation of mTORC1 signaling upon Kdm6a loss. mTOR activation appeared to be critical to suppress cell death as blunting mTOR signaling by Kdm6a re-expression promoted caspases-3/7 activation in vitro and in vivo. Notably, CRISPR-mediated Deptor deletion rescued the Kdm6a phenotype, while Deptor overexpression abrogated Kdm6a-induced liver tumorigenesis. Moreover, we also found a strong sensitivity of Kdm6a-deficent tumors to mTOR inhibitors. Finally, analyses of human HCCs showed a strong positive correlation between KDM6A and DEPTOR expression, further suggesting a direct relationship in human tumorigenesis. In addition, utilizing a pancreatic ductal adenocarcinoma (PDAC) mouse model we could demonstrate that shRNA-mediated silencing of Kdm6a synergizes with oncogenic KrasG12D to drive pancreatic tumor formation and we could recapitulate the tumor-suppressive function of Kdm6a via mTOR regulation this tumor model and tumor type.  Hence, our results link KDM6A-dependent epigenetic remodeling to mTOR signaling and provide a potential therapeutic strategy for KDM6A-deficient tumors.
date: 2021
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/29026/1/REVIA_Dissertation.pdf
identifier: DOI:10.11588/heidok.00029026
identifier: urn:nbn:de:bsz:16-heidok-290263
identifier:   Revia, Steffie  (2021) KDM6A is an epigenetic gatekeeper of mTORC1 signaling in cancer.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/29026/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng