POLR1F promotes proliferation and stemness of anaplastic thyroid cancer by activating F2R/p38 MAPK signaling

Anaplastic thyroid cancer (ATC) is one of the most aggressive cancers characterized by a rapid growth rate. Dysregulation of RNA polymerase (Pol) is critical for cancer development. However, little is known about its role and mechanism in ATC. In the present study, the expression of Pol family members is screened in a large-cohort proteome containing 113 ATCs and 20 normal thyroid samples. Combined with the mRNA levels and gene dependency scores, we find that RNA Polymerase I Subunit F (POLR1F) is significantly upregulated in ATC tissues with the strongest gene effect among the Pol family members. The results are confirmed in ATC tissues and cell lines, revealing that POLR1F mainly locates in the nucleus and expresses stronger than that in normal thyrocytes. Silencing POLR1F in ATC cell lines significantly inhibit cell proliferation, colony formation, and sphere sizes. POLR1F knockdown dramatically reduces ATC tumor growth in both zebrafish and nude mouse xenograft models. RNA sequencing reveals that the coagulation factor thrombin receptor (F2R) is a downstream target of POLR1F, which participates in the p38 MAPK pathway. POLR1F promotes the H3K4 methylation at the F2R promoter by reducing the binding of demethylase KDM5C to H3K4me3, thereby enhancing F2R transcription. These results demonstrate that POLR1F maintains ATC stemness and growth by activating F2R/p38 MAPK signaling, shedding light on the essential role of POLR1F in ATC progression.