The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer.

FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.

The prognostic significance of FOXC2 gene expression in cancer: A comprehensive analysis of RNA-seq data from the cancer genome atlas.

The FOXC2 transcription factor is a key regulator of tumor progression in many cancer types. Known to exhibit an array of oncogenic functions when dysregulated, FOXC2 has emerged as a useful biomarker for predicting disease aggression and patient outcome. In this regard, increased expression and nuclear localization of FOXC2 protein in tumor tissue have become well-established as poor prognostic factors for many cancer types. However, whether FOXC2 gene expression can serve as a similarly useful RNA-level biomarker has remained largely unexplored. Therefore, we conducted a comprehensive analysis of TCGA RNA-seq data to evaluate whether FOXC2 gene expression levels in primary tumor biopsies correlate with patient outcome. We report herein that increased expression of FOXC2 RNA in tumor tissue is a poor prognostic factor for patient survival in many cancer types. Moreover, we also found that FOXC2 gene expression predicts cancer patient response to several commonly prescribed chemotherapeutics. Together, these data highlight FOXC2 RNA expression in tumor tissue as an important biomarker with prognostic significance for solid tumors of diverse origin.

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness.

BACKGROUND/AIM: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. MATERIALS AND METHODS: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. RESULTS: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. CONCLUSION: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies.