Beyond mutations: New study reveals alternative route to cancer

Cancers can develop through epigenetic pathways even without driver gene mutations (DGMs), according to a study from Science Tokyo. Researchers uncovered the YAP1–TEAD–TET1 axis, which triggers DNA demethylation and activates multiple oncogenes in hepatocellular carcinoma. Suppressing TET1 reduced tumor formation in mice, while analysis of human liver disease data supported the relevance of these findings. This study reveals an alternative epigenetic route to cancer development and offers new insights into DGM-negative cancers.

Most cancers develop from genetic abnormalities that activate proto-oncogenes or inactivate tumor suppressor genes. To identify the changes that drive cancer onset, scientists worldwide use next-generation sequencing, which enables comprehensive analysis of whole genomic and transcriptomic data and aims to uncover driver gene mutations (DGMs).

While DGMs have been identified in the vast majority of cancers, a subset lacks these canonical mutations. The underlying mechanisms that allow these tumors to develop, therefore,  remain poorly understood. Understanding how cancer develops without DGMs could reveal alternative routes to tumor formation.

In an effort to better understand this mechanism, a research team led by Professor Hiroshi Nishina, Assistant Professor Yoshimi Okamoto-Uchida, and doctoral student Misaki Kosaka (at the time of the study), from the Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (Science Tokyo), Japan, identified a novel oncogenic mechanism involving DNA demethylation. Their findings, published in Volume 9 of the journal Communications Biology on September 17, 2026, examines how YAP1-TEAD signaling can promote hepatocellular carcinoma (HCC) without canonical DGMs. This study was conducted in collaboration with Professor Teppei Shimamura from the Medical Research Laboratory, Institute of Integrated Research, Science Tokyo; Special Researcher Haruka Hirose from the National Cancer Center Research Institute, Japan; Professor Yutaka Suzuki and Special Associate Professor Akinori Kanai from The University of Tokyo, Japan; Professor Akira Suzuki and Lecturer Miki Nishio from Kobe University Graduate School of Medicine, Japan; and Professor Tomohiko Maehama from Showa Medical University School of Medicine, Japan.

“We hypothesized that a complex composed of the transcriptional coactivator YAP1 and the transcription factor TEAD could promote cancer development not through genomic DNA mutations but by inducing DNA demethylation, and we set out to test this hypothesis,” explains Okamoto-Uchida.

The researchers created a mosaic mouse model by activating YAP1 in a subset of liver cells via hydrodynamic tail-vein injection. They analyzed the resulting tumors using whole-exome sequencing to identify mutations along with DNA methylation analyses to understand epigenetic changes. The tumors showed no detectable canonical DGMs, while the methylation analyses revealed widespread DNA demethylation associated with the activation of multiple oncogenes. The team then reduced the expression of the Tet1 gene, which encodes Ten-eleven translocation (TET1), an enzyme that promotes DNA demethylation, to test its role in tumor development.

The team’s innovative approach confirmed that YAP1-TEAD activation enhanced the expression of TET1, thereby promoting DNA demethylation and the activation of multiple cancer-related genes. The findings also showed that suppressing TET1 function reduces tumor formation. Spatial transcriptomic analysis further identified a TET1-high subpopulation of HCC cells interacting with other hepatic cell types. “We observed that the expression of TET1 increased, promoting the activation of multiple cancer-related genes, and that suppressing TET1 function reduced tumor formation,” says Okamoto-Uchida.

Furthermore, an analysis of human data revealed elevated YAP1–TEAD–TET1-associated signatures in hepatocytes from patients with Fontan-associated liver disease, a condition associated with HCC and a lower frequency of canonical DGMs. These findings reveal an epigenetic pathway to HCC development that does not depend on canonical DGMs.

Future research could examine whether similar epigenetic pathways operate in other DGM-negative cancers, identify the signals that initiate YAP1-TEAD activation, and clarify how TET1 selects its target genes. These questions may help establish whether the pathway offers potential therapeutic targets for further investigation.

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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”