Ying Zhang^1,2*, Kaijing Chen³*, Seng Chuan Tang^1,3*, Yichao Cai¹*, Akiko Nambu¹, Yi Xiang See^1,3, Chaoyu Fu⁴, Anandhkumar Raju⁵, Benjamin Lebeau³, Zixun Ling¹, Jia Jia Chan¹, Yvonne Tay^1,6, Marek Mutwil³, Manikandan Lakshmanan⁵, Greg Tucker-Kellogg^7,8, Chng Wee Joo^1,9,10,11, Daniel G. Tenen^1,12, Motomi Osato¹, Vinay Tergaonkar^5,12, Melissa Jane Fullwood^1,3,13
1Cancer Science Institute of Singapore, National University of Singapore, 14 Medical
Drive, 117599 Singapore.
²Genome Institute of Singapore, Agency for Science, Technology and Research
(A*STAR), 138672 Singapore.
³School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive,
637551 Singapore.
⁴Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1,
117411 Singapore.
⁵Laboratory of NFkB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency
for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673
Singapore.
⁶Department of Biochemistry, Yong Loo Lin School of Medicine, National University of
Singapore (NUS), 8 Medical Drive, MD7, 117596 Singapore.
⁷Department of Biological Sciences, National University of Singapore, 16 Science
Drive 4, 117558 Singapore.
⁸Computational Biology Programme, Faculty of Science, National University of
Singapore, 16 Science Drive 4, 117558 Singapore.
⁹Department of Medicine, Yong Loo Lin School of Medicine, National University of
Singapore, 117597 Singapore.
¹⁰NUS Centre for Cancer Research (N2CR), Centre for Translational Medicine, 14
Medical Drive, 117599 Singapore.
¹¹Department of Hematology-Oncology, National University Cancer Institute of
Singapore (NCIS), National University Health System (NUHS), 1E Kent Ridge Road,
119228 Singapore.
¹²Harvard Stem Cells Institute, Harvard Medical School, Boston, MA 02115, USA.
¹³Institute of Molecular and Cell Biology, Agency for Science, Technology and
Research (A*STAR), 61 Biopolis Drive, Proteos, 138673 Singapore.
* These authors contributed equally

Human silencers have been identified as regulators of developmental gene expression, but their functional importance, including their potential to form “super-silencers” and their link to cancer progression, remains unclear. In this study, we demonstrate that two silencer components of the FGF18 gene can cooperate through compensatory chromatin interactions to form a “super-silencer.” These “super-silencers” play a crucial role in controlling cancer progression, providing a compelling rationale for targeting them in cancer therapy. To disrupt these “super-silencers,” we employed a combination treatment of an EZH2 inhibitor, GSK343, and a REST inhibitor, X5050, referred to as “GR.” Remarkably, GR treatment caused a substantial loss of topologically associating domains (TADs) and chromatin loops, while synergistically upregulating super-silencer-controlled genes associated with the cell cycle, apoptosis, and DNA damage. These changes resulted in significant anticancer effects in vivo. Using time-course Hi-C and RNA-Seq analyses, we observed that the reduction in CTCF and TOP2A levels might explain the 3D genome reorganization induced by GR treatment. Overall, our findings provide evidence of a “super-silencer” and demonstrate that GR can effectively disrupt these elements, potentially leading to cancer ablation. This work has recently been accepted by Nature Structural & Molecular Biology.
 

super-silencer,chromatin interactions,cancer