The Forkhead factor FoxQ1 influences epithelial differentiation

Abstract

The Forkhead family of transcription factors comprises numerous members and is implicated in various cellular functions, including cell growth, apoptosis, migration, and differentiation. In this study, we identified the Forkhead factor FoxQ1 as increased in expression during TGF-β1 induced changes in epithelial differentiation, suggesting functional roles of FoxQ1 for epithelial plasticity. The repression of FoxQ1 in mammary epithelial cells led to a change in cell morphology characterized by an increase in cell size, pronounced cell-cell contacts, and an increased expression of several junction proteins (e.g., E-cadherin). In addition, FoxQ1 knock-down cells revealed rearrangements in the actin-cytoskeleton and slowed down cell cycle G1-phase progression. Furthermore, repression of FoxQ1 enhanced the migratory capacity of coherent mammary epithelial cells. Gene expression profiling of NM18 cells indicated that FoxQ1 is a relevant downstream mediator of TGF-β1-induced gene expression changes. This included the differential expression of transcription factors involved in epithelial plasticity, for example, Ets-1, Zeb1, and Zeb2. In summary, this study has elucidated the functional impact of FoxQ1 on epithelial differentiation.

Forkhead factors regulate epithelial plasticity: Impact on cancer progression

“…47 Initially it has been documented, that aberrant FoxQ1 activity promotes cancer progression by affecting apoptosis and angiogenesis. 49 Independent studies additionally suggest that FoxQ1 affects epithelial cell differentiation, 50 and promotes metastasis formation of different carcinoma cells. 51,52 In non-tumorigenic mammary gland epithelial cells (NMuMG), FoxQ1 is induced by TGFβ1 and represses several epithelial-characteristic factors, including proteins of junctional complexes (e.g., E-cadherin, Occludin) as well as the epithelialspecific and cytoskeletal-associated protein Villin-1.…”

“…Consistently, the transcription factor Ets-1, a known modulator of TGFβ1-induced changes in epithelial differentiation and transactivator of Zeb1 and Zeb2 in these cells 53 is markedly suppressed upon FoxQ1 knockdown. 50 Therefore, FoxQ1 may represent an early upstream mediator of TGFβ1 signaling and might regulate epithelial cell features probably interacting with other transcription factors.…”

“…In this aspect, our own results suggest that TGFβ1 signaling regulates a whole set of Fox-factors during cytokineinduced epithelial dedifferentiation, including the repression of FoxA2 and a concomitant increase in FoxQ1 expression. 50 As a common target of the mentioned Fox-factors and due to its established role as tumor-suppressor, E-cadherin certainly represents an attractive and functionally relevant downstream target, which is further emphasized by the finding that E-cadherin expression affects CD44 and CD24 expression, putative markers of tumorigenic breast cancer stem-cells. 52,63 In contrast, the described changes of bona fide epithelial marker expression (e.g., E-cadherin, ZO-1), does not strictly correlate with metastatic capacity as indicated by a study of of respective mice instead of applying the cells directly into the blood circulation via tail-vein injection.…”

FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion

“…Forkhead box Q1 (FOXQ1, also termed HFH1) is a member of the forkhead transcription factor family (9), which is involved in a variety of biological processes, including epithelial differentiation (10), cell cycle progression (11), embryonic stem cell differentiation (12), metabolism (13,14) and carcinogenesis (15)(16)(17). As one of the first forkhead genes to be investigated, FOXQ1 has been demonstrated to be involved in metabolism, aging (18) and carcinogenesis (19).…”

Bone and Cartilage from Stem Cells: Growth Optimalization and Stabilization of Cell Phenotypes

“…The mir-143 mediated suppression of all the above listed genes are expected when chondrocytes are dedifferentiated. Mir-140-3p was down-regulated and coupled to the modulation of gene transcripts like KLF4 (transcription factor activated by the Wnt-pathway) (Saulnier, Puglisi et al 2011) , FOXQ1 (serves as a down-stream mediator of TGF 1 signalling) (Feuerborn, Srivastava et al 2011), CITED4 (serves as a co-activator of CEP/p300, TFAP2, and SMAD4 transcription factors involved in stem cell differentiation) (Braganca, Swingler et al 2002), and PTCH4 (receptor activated by Hh, thus stimulating the SMO-GLI pathway of gene transcription) (Takebe, Harris et al 2011). …”