YY1 downregulation underlies therapeutic response to molecular targeted agents
During targeted treatment, oncogene-addicted tumor cells often evolve from an initial drug-sensitive state through a drug-tolerant persister bottleneck toward the ultimate emergence of drug-resistant clones. The molecular basis underlying this therapy-induced evolutionary trajectory has not yet been completely elucidated. Here, we employed a multifaceted approach and implicated the convergent role of transcription factor Yin Yang 1 (YY1) in the course of diverse targeted kinase inhibitors. Specifically, pharmacological perturbation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway resulted in the downregulation of YY1 transcription, which subsequently resumed upon therapeutic escape. Failure to decrease YY1 subverted cytotoxic effects, whereas elimination of residual YY1 maximized anticancer efficacy and forestalled the emergence of drug resistance. Mechanistically, YY1 was uncovered to dictate cell cycle and autophagic programs. Immunohistochemical analysis on a wide spectrum of clinical specimens revealed that YY1 was ubiquitously expressed across lung adenocarcinomas and exhibited anticipated fluctuation in response to corresponding RTK/MAPK inhibition. These findings advance our understanding of targeted cancer management by highlighting YY1 as a determinant node in the context of genotype-directed agents.
Authors
- Tianqing Chu (ORCID: https://orcid.org/0000-0002-0744-0397)
- Ying Shen (ORCID: https://orcid.org/0000-0003-0656-7377)
- Junhong Jiang (ORCID: https://orcid.org/0000-0001-6205-9567)
- Jingyu Zang (ORCID: https://orcid.org/0000-0001-9416-2323)
- Yujie Fu (ORCID: https://orcid.org/0000-0003-4828-9459)
- Mei‐Chun Cai (ORCID: https://orcid.org/0000-0003-2861-6539)
- Xiaojing Zhao (ORCID: https://orcid.org/0000-0001-5571-9192)
- Guanglei Zhuang (ORCID: https://orcid.org/0000-0003-3088-177X)
- Kaiyan Ye (ORCID: https://orcid.org/0009-0000-3920-8181)
- Li Tan (ORCID: https://orcid.org/0000-0002-1199-9046)
- Pengfei Ma (ORCID: https://orcid.org/0000-0003-3061-1454)
- Zhuang Yu (ORCID: https://orcid.org/0000-0003-1676-135X)
- Shichao Zhou (ORCID: https://orcid.org/0009-0008-9229-6190)
- Jie Wu (ORCID: https://orcid.org/0000-0003-3927-4765)
- Chenyang Dai (ORCID: https://orcid.org/0000-0001-9609-0343)
- Jin Liu (ORCID: https://orcid.org/0000-0002-2026-2513)
- Haijiao Lu
- Qing Zhang (ORCID: https://orcid.org/0000-0002-9987-5661)
- Lan Wang (ORCID: https://orcid.org/0009-0005-3726-5701)
Institutions
- Qingdao University (CN)
- Tongji University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Renji Hospital (CN)
- Shanghai Chest Hospital (CN)
- Soochow University (CN)
- Zhejiang Cancer Hospital (CN)
- Jiangyin People's Hospital (CN)
- Shanghai Cancer Institute (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Affiliated Hospital of Qingdao University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Shanghai Pulmonary Hospital (CN)
- Hangzhou Cancer Hospital (CN)
- The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1038/s41419-024-07239-8
- Citations
- 7
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Shanghai Municipal Education Commission
- Science and Technology Commission of Shanghai Municipality
- Higher Education Discipline Innovation Project