FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor

Abstract

The role of Forkhead Box F1 (FoxF1) transcription factor in carcinogenesis is not well characterized. Depending on tissue and histological type of cancer, FoxF1 was shown to be either oncogene or tumor suppressor. Alveolar rhabdomyosarcoma (RMS) is the most aggressive pediatric soft tissue sarcoma. While FoxF1 is highly expressed in alveolar RMS, the functional role of FoxF1 in RMS is unknown. The present study demonstrates that expression of FoxF1 and its closely related transcription factor FoxF2 are essential for rhabdomyosarcoma tumor growth. Depletion of FoxF1 or FoxF2 in rhabdomyosarcoma cells decreased tumor growth in orthotopic mouse models of RMS. The decreased tumorigenesis was associated with the reduced tumor cell proliferation. Cell cycle regulatory proteins Cdk2, Cdk4/6, Cyclin D1 and Cyclin E2 were decreased in FoxF1- and FoxF2-deficient RMS tumors. Depletion of either FoxF1 or FoxF2 delayed G1-S cell cycle progression, decreased levels of phosphorylated Rb and increased protein levels of the CDK inhibitors, p21Cip1 and p27Kip1. Depletion of both FoxF1 and FoxF2 in tumor cells completely abrogated RMS tumor growth in mice. Overexpression of either FoxF1 or FoxF2 in tumor cells was sufficient to increase carcinogenesis in orthotopic RMS mouse model. FoxF1 and FoxF2 directly bound to and repressed transcriptional activity of p21Cip1 promoter through −556/−545 bp region, but did not affect p27Kip1 transcription. Knockdown of p21Cip1 restored cell cycle progression in the FoxF1- or FoxF2-deficient tumor cells. Altogether, FoxF1 and FoxF2 promoted RMS tumorigenesis by inducing tumor cell proliferation via transcriptional repression of p21Cip1 gene promoter. Due to robust oncogenic activity in RMS tumors, FoxF1 and FoxF2 may represent promising targets for anti-tumor therapy.

Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway

“…Several Fox family members have been shown to regulate cyclin-dependent kinase inhibitor (CDKI) proteins [14,23–25]. We therefore tested whether Shh-induced proliferation in iMEFs is CDK-dependent and sensitive to the potent pharmacologic CDKI, palbociclib.…”

Comprehensive analysis of lncRNA‐TF crosstalks and identification of prognostic regulatory feedback loops of glioblastoma using lncRNA/TF‐mediated ceRNA network

“…We performed the subpathway enrichment to TFs in module 1 ( Figure 5C) and showed that 4 subpathways were enriched because of the fewer genes. 27 Module 2 encompassed 44 nodes (22 lncRNAs and 22 TFs) and 120 edges ( Figure 5D). Kaur stemness, invasion and tumorigenicity of GBM.…”

“…26 Additionally, FOXF2 has also been demonstrated to suppress the transcription of p21Cip1 CDK inhibitor with FoxF1, which synergistically promoted rhabdomyosarcoma carcinogenesis. 27 Module 2 encompassed 44 nodes (22 lncRNAs and 22 TFs) and 120 edges ( Figure 5D). Subpathway enrichment results showed that this module was related to basal functions, "TGF-beta signaling pathway" and "Jak-STAT signaling pathway" (Figure 5F).…”

Bioinformatic analysis of the prognostic value and potential regulatory network of FOXF1 in papillary thyroid cancer

“…In lung cancer, FOXF1 modulates the anti‐malignant effects of mesenchymal stem cells (MSCs) fusion‐induced reprogramming on lung cancer cells . In contrast, some recent studies revealed that FOXF1 might also act as an oncogene in some cancers, such as colorectal cancer and rhabdomyosarcoma . These findings imply that the functional role of FOXF1 might be cancer‐specific.…”