FOXK2 is a repressor that interacts with various corepressor complexes to target the hypoxic response.
Major finding: FOXK2 is a repressor that interacts with various corepressor complexes to target the hypoxic response.
Clinical relevance: FOXK2 downregulation is associated with a poor prognosis in patients with breast cancer.
Impact: FOXK2 is a putative tumor suppressor that may play a key role in breast cancer progression.
Forkhead box K2 (FOXK2) is a developmental transcription factor, but its role in tumorigenesis has not been elucidated. Shan and colleagues found that FOXK2 physically interacted with multiple transcriptional corepressor complexes, including NCoR/SMRT, SIN3A, NuRD, and REST/CoREST, to promote transcriptional repression. Chromatin immunoprecipitation sequencing revealed that each FOXK2-corepressor complex regulated a distinct set of target genes, including genes involved in cancer-related processes such as hypoxia and metastasis, and EZH2. Consistent with these findings, FOXK2 suppression increased the proliferation and colony-forming ability of breast cancer cells, and FOXK2-deficient cells exhibited characteristics of epithelial–mesenchymal transition (EMT). Depletion of FOXK2 or components of the corepressor complexes increased the invasive ability of breast cancer cells, whereas expression of hypoxia inducible factor 1β (HIF1β) suppressed the increase in invasion. In vivo, depletion of FOXK2 or its corepressors in an orthotopic breast cancer model resulted in increased growth of the primary tumor as well as metastatic lesions, whereas HIF1α depletion partially reversed the effects on metastasis. Altogether, these findings suggest that FOXK2/corepressor complexes suppress breast tumorigenesis. FOXK2 was transcriptionally upregulated by ERα and downregulated by HIF1β, indicating that the hypoxia pathway may negatively regulate FOXK2 expression. Mechanistically, HIF1β enhanced transcription of EZH2, which negatively regulated FOXK2, and conversely, FOXK2 negatively regulated EZH2 and HIF1β. To understand the clinical relevance of these findings, FOXK2 expression was assessed in paired cancer and normal adjacent samples from 25 patients with breast cancer. FOXK2 was downregulated in 18 of the breast carcinomas, and was inversely correlated with expression of EZH2 and HIF1β. Moreover, FOXK2 was downregulated during cancer progression and associated with a poor prognosis. Collectively, these findings suggest a tumor suppressive role for FOXK2 in breast cancer and identify a reciprocal feedback loop between FOXK2 and HIF1β/EZH2.