Oncotarget

Research Papers:

Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth

Tatjana Pandzic, Veronica Rendo, Jinyeong Lim, Chatarina Larsson, Jimmy Larsson, Ivaylo Stoimenov, Snehangshu Kundu, Muhammad Akhtar Ali, Mats Hellström, Liqun He, Anders M. Lindroth and Tobias Sjöblom _

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Oncotarget. 2017; 8:98646-98659. https://doi.org/10.18632/oncotarget.21713

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Abstract

Tatjana Pandzic1, Veronica Rendo1, Jinyeong Lim2, Chatarina Larsson1, Jimmy Larsson1, Ivaylo Stoimenov1, Snehangshu Kundu1, Muhammad Akhtar Ali1, Mats Hellström1, Liqun He1, Anders M. Lindroth2 and Tobias Sjöblom1

1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

2Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang-si, Republic of Korea

Correspondence to:

Tobias Sjöblom, email: [email protected]

Keywords: colorectal cancer; PRDM2; genome editing

Received: May 27, 2017    Accepted: August 26, 2017    Published: October 09, 2017

ABSTRACT

The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.


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