Aberrant accumulation of Kras-dependent pervasive transcripts during tumor progression renders cancer cells dependent on PAF1 expression
Xinhong Liu,
Xiangzheng Liu,
Yingxue Du,
Di Zou,
Chen Tian,
Yong Li,
Xun Lan,
Charles J. David,
Qianwen Sun,
Mo Chen
Affiliations
Xinhong Liu
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
Xiangzheng Liu
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
Yingxue Du
Tsinghua University School of Life Sciences, Beijing 100084, China
Di Zou
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
Chen Tian
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
Yong Li
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China
Xun Lan
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
Charles J. David
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
Qianwen Sun
Tsinghua University School of Life Sciences, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
Mo Chen
State Key Laboratory of Molecular Oncology, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing 100084, China; Corresponding author
Summary: KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.
