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Peer-reviewedCC BY 4.0PLOS Computational Biology

Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression

  • Ping Xu1
  • Zile Luo2
  • Xi Chen3
  • Zhongyang Yuan4
  • Le Cheng5
  • Yi Yang6
  • Hongcheng Lin7
  • Qiong Zhang8
  • Pengfei Qin9
9 affiliations
  1. 1BGI Research, Chongqing, China
  2. 2BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
  3. 3College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
  4. 4State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen, China
  5. 5BGI Research, Kunming, China
  6. 6Department of General Surgery (Department of Coloproctology), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  7. 7Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  8. 8Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  9. 9Department of Obstetrics and Reproductive Medicine, Affiliated Hospital of Yunnan University, Kunming, Yunnan, China
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Abstract

The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This “local activation-global suppression” paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance. Author summary: Why does a molecule known for shutting down gene activity actually help tumors survive chemotherapy? This intriguing paradox motivated our investigation. Using single-cell technologies to analyze patient tumor samples, we found that in chemotherapy-resistant colorectal cancer cells, the non-coding RNA 7SK selectively amps up a specific set of proliferation-driving genes through the JUN network, pressing the accelerator on tumor growth. At the same time, it broadly dampens overall gene expression disorder, which quiets immune alarm signals and creates a “cold” tumor environment that evades immune attack. This dual strategy of local activation paired with global suppression helps resistant clones thrive under therapeutic pressure. Remarkably, we observed the same mechanism operating across multiple cancer types, suggesting that 7SK’s role is not a cancer-specific quirk but a conserved survival program. Our findings reframe 7SK from a simple repressor to a master conductor of transcriptional balance in cancer. By uncovering 7SK’s dual role, we lay a foundation for future therapeutic strategies aimed at disrupting this mechanism to overcome drug resistance.

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Cite

BibTeXRIS
BibTeX
@article{xu2026noncoding,
  title = {{Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression}},
  author = {Ping Xu and Zile Luo and Xi Chen and Zhongyang Yuan and Le Cheng and Yi Yang and Hongcheng Lin and Qiong Zhang and Pengfei Qin},
  journal = {PLOS Computational Biology},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pcbi.1014749},
  url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014749},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression
AU  - Ping Xu
AU  - Zile Luo
AU  - Xi Chen
AU  - Zhongyang Yuan
AU  - Le Cheng
AU  - Yi Yang
AU  - Hongcheng Lin
AU  - Qiong Zhang
AU  - Pengfei Qin
PY  - 2026
DA  - 2026/09/08
JO  - PLOS Computational Biology
DO  - 10.1371/journal.pcbi.1014749
UR  - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014749
AB  - The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This “local activation-global suppression” paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance. Author summary: Why does a molecule known for shutting down gene activity actually help tumors survive chemotherapy? This intriguing paradox motivated our investigation. Using single-cell technologies to analyze patient tumor samples, we found that in chemotherapy-resistant colorectal cancer cells, the non-coding RNA 7SK selectively amps up a specific set of proliferation-driving genes through the JUN network, pressing the accelerator on tumor growth. At the same time, it broadly dampens overall gene expression disorder, which quiets immune alarm signals and creates a “cold” tumor environment that evades immune attack. This dual strategy of local activation paired with global suppression helps resistant clones thrive under therapeutic pressure. Remarkably, we observed the same mechanism operating across multiple cancer types, suggesting that 7SK’s role is not a cancer-specific quirk but a conserved survival program. Our findings reframe 7SK from a simple repressor to a master conductor of transcriptional balance in cancer. By uncovering 7SK’s dual role, we lay a foundation for future therapeutic strategies aimed at disrupting this mechanism to overcome drug resistance.
SN  - 1553-7358
ER  -