PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Thyroid cancer (TC) is the most common endocrine malignancy.
• PARP inhibitors show promise beyond BRCA-mutant cancers, but their mechanisms in TCs are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of niraparib in thyroid cancers.
• To explore the potential of combining niraparib with NF-κB inhibitors.

Main Methods:

• Assessing DNA damage accumulation induced by niraparib in TCs.
• Analyzing niraparib's effect on DIMT1 transcription and Pol II pausing.
• Investigating niraparib's impact on NF-κB signaling pathway activation.
• Evaluating the synergistic anti-tumor effects of niraparib and bortezomib in vitro and in vivo.

Main Results:

• Niraparib promotes DNA damage accumulation in TCs.
• Niraparib inhibits DIMT1 transcription via PAR-dependent Pol II pausing, causing global translation inhibition.
• Niraparib activates the NF-κB pathway by inhibiting p65 PARylation, reducing its ubiquitination and degradation.
• Bortezomib significantly enhances niraparib's anti-tumor efficacy in TCs.

Conclusions:

• Niraparib exerts anti-tumor effects in TCs by inducing DNA damage and inhibiting DIMT1 transcription.
• Niraparib modulates NF-κB signaling, offering a potential therapeutic target.
• These findings support the use of PARP inhibitors in thyroid cancers, even those without BRCA mutations, and suggest combination strategies.