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Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells
Claire D James1, Siddharth Saini2, Fatmata Sesay2
1Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USA.
Cancers
|January 30, 2021
Summary
High-risk human papillomaviruses (HR-HPV) promote cancer by disrupting the DREAM complex. Restoring this complex in HR-HPV-positive cells inhibits proliferation, offering a potential therapeutic strategy for HPV-driven cancers.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- High-risk human papillomaviruses (HR-HPV) are linked to 5% of human cancers, including cervical, ano-genital, and head and neck carcinomas.
- HR-HPV oncoproteins, particularly E7, target host tumor suppressors like retinoblastoma protein (pRb) and its relatives (p107, p130) to drive cancer progression.
- The E7 protein's LxCxE motif binds RB proteins, disrupting cell-cycle control and the DREAM transcriptional repressor complex.
Purpose of the Study:
- To investigate the role of DREAM complex disruption in HR-HPV-driven tumorigenesis.
- To explore the therapeutic potential of restoring DREAM complex function in HR-HPV-positive cancers.
Main Methods:
- Studied the interaction between the LIN52 adaptor protein within the DREAM complex and p130.
- Engineered a LIN52 mutant (LIN52-S20C) with an altered motif to enhance binding to p130.
- Assessed the impact of this mutation on DREAM complex assembly and cell proliferation in HPV-positive keratinocytes and cervical cancer cells.
Main Results:
- LIN52 binds p130 via an E7-like LxSxE motif; altering this to LxCxE (LIN52-S20C) enhances p130 binding.
- LIN52-S20C partially restored DREAM complex assembly in HR-HPV-positive cells.
- Restoration of the DREAM complex led to inhibited proliferation in these cancer cells.
Conclusions:
- Disruption of the DREAM complex by HR-HPV E7 is a key mechanism promoting cellular proliferation in HR-HPV-driven cancers.
- Restoring the DREAM complex in HR-HPV-positive cells demonstrates therapeutic potential for treating associated cancers.
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