Elena Tschumak - Influence of FOX genes on aging and aging-associated diseases

FOXP2 regulates proto-oncogenes p21WAF1 / RAS 1, BCL-2, HES1 and other cancer-relevant genes.Gascoyne et al. (2015) demonstrated in „The forkhead transcription factor FOXP2 is required for regulation of p21WAF1 / CIP1 in 143B osteosarcoma cell growth arrest“ with the help of human osteosarcoma cell cultures and normal human osteoblasts that the forkhead transcription factor FOXP2 regulates proto-oncogenes p21WAF1 and CIP1. These proto-oncogenes are required for osteosarcoma cell growth arrest. lncRNA-p21 influences cell proliferation and carcinogenesis via vβ-catenin and JunB. The lncRNA HULC is highly expressed in age related colorectal carcinomas and UCA1 is highly expressed in bladder transitional cell carcinoma by modulating p27 level and can affect cellular senescence.(Parket al., 2011; Smith-Vikos and Slack, 2012) The decrease of growth factor level as well as MAPK reduction induces FOXP2 expression. In turn FOXP2 expression triggers cyclin-dependent kinase inhibitor p21WAF1 / CIP1 expression. It is known that p21 is one of the p53 target genes. (Deiry et al., 1994)19ARF/p53 and p16INK4a/Rb stop cancer cells from proliferation and play an important role in cellular senescence.

During these experiments, the DMEM-cultured and ATCC-derived osteosarcoma cell lines were treated with the IKK pathway inhibitor VII, the MAPK pathway inhibitor, the LY-294002 PI3K pathway inhibitor, the 117082 NF-kappa B pathway inhibitor, the Notch signalling pathway inhibitor or with the DMSO vesicle. Then the alkaline phosphatase and MTS assays were done and 405nm absorbance was measured. Other methods were RNA isolation, cDNA preparation and real-time PCR, protein isolation, immunoblotting, chromatin immunoprecipitation and flow cytometric analysis of the cell cycle distribution. The authors found a link between the 7-time increased FOXP2 expression in murine bone 48 h after treatment and the decreased growth of osteosarcoma cell lines. Unlike mesenchymal tissue osteoblasts did not require RUN involvement in FOXP2 induction. (Zhao et al., 2014) In neuroblastoma cells growth arrest was not accompanied by FOXP2 induction. Cyclin-dependent kinase inhibitors such as p21WAF1, p27KIP1, CIP1CDKN1A and CDKN1B organize CDK inhibition. These experiments also demonstrated that FOXP2 induces CDKN1A / p21 expression in osteoblasts and serves as a primary trigger for cell growth arrest. FOXP2 reduction resulted in strong CDKN1A / p21 and slight CDK4 decline and showed no effect on p53 level. Increased p53 / p21 level had no effect on FOXP-2 level. Immunoprecipitation did not show direct FOXP2 / p21 binding sites and it was demonstrated that although increased FOXP2 expression was accompanied by concomitant IL-6 expression but FOXP2 did not controls p21 expression via IL-6, p21 induction by the FOXP2 takes place indirectly. This is still to be studied. The researchers found a correlation between Lhx8 deficiency factor and FOXP2 expression. There may be a relationship between the FOXP2 and the Soxp2.

Yan X et al. showed 2015 in „Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion“ that FOXP2 level in human hepatocellular carcinoma cells is significantly reduced compared to adjacent non-tumor tissue. They used Western blot, transwell assays and immunohistochemistry to measure FOXP2 expression in HCC and in adjacent normal tissues of 50 patients. Their results showed that FOXP2 expression was down-regulated in HCC tumor tissue and that FOXP2-level decrease correlated with poor survival rates. FOXP2 could decrease cell invasion and affect the expression of vimentin and OXE-cadherin.

Since the study by Schroeder and Myers (2008) has emphasized the importance of cell-specific FoxP expression it is especially important to measure it in different tissues and to take a closer look at its cell-specific interaction mechanisms. Chiu et al. (2014) described how FOXP2 inhibits the ERK / MAPK (HSPB7), NOS1, KCNJ15 and SHH pathways (PTCH1) and Vernes et al. (2011) and Ayub et al. (2013) how it influences the oncogene CDK8. FOXP2 effects Bcl-2 expression which seems to be involved in pro-caspase activation and apoptosis. (Devanna et al., 2014). Spiteri et al. (2007) described the cancer-related actin-binding protein genes TAGLN, NOS1, LBR, KCNJ15 and ANK1 as additional FOXP2 target genes. FP2 affects the proto-oncogene C-MET by binding its regulator the AP1-NFAT complex. It also affects the p53 which in turn binds to C-MMET. (Mukamel et al., 2011) (Ho and Crabtree, 2006). MAPK and TGF-β pathways are modified by lncPINT, which is also affected by the with PRC2 interacting p53.

FOXP1 functions, parallels to FOXP2Like FOXP2's, FOXP1 plays an important role in brain development, because its haploinsufficiency is associated with speech deficits and autism. (Tamura et al., 2003; Le Fevre et al., 2013; Horn et al., 2010; Hamdan et al., 2010; Bacon and Rappold, 2011; Lien et al., 2001; Pariani et al, 2009; Chien et al., 2013; Palmerbo et al., 2013; Carr et al, 2010; Vargha-Khadem et al, 1998; Watkins et al. Brain, 2002; Reimers-Kipping et al. al., 2011; Scharff et Petri, 2011; Li et al., 2015; Song et al., 2015) However, according to „Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders“ (2017) of Sollis et al. the R514H mutation of the FOXP1 gene has a wider and heavier disease manifestation than corresponding p.R553H mutation of the FOXP2 gene. Other functions of the FOXP1 gene were described by Rousso et al. (2016), Wang et al. (2003, 2004), Xing et al.(2017) and Taskapilioglu et al. (2016). According to the recent study by Fröhlich et al. „Foxp1 expression is essential for sex-specific murine neonatal ultrasonic vocalization“ (2017), Foxp1 expression is essential for sex-specific murine neonatal ultrasound vocalization. This study could be of clinical importance because boys are more affected by utism and other speech and speech deficits than girls. They showed that Foxp1 and the androgen receptor are co-expressed in striatal neurons and that brain-specific androgen receptor KO (ArNesCre) mice have a reduced Foxp1 expression in the striatum and an increased Foxp2 level. Oestrogen also reduced the FOXP1 level in breast cancer tissue. (Shigekawa et al., 2011) FOXP3 significance for Alzheimer's disease and for apoptosisBaruch et al. (2015) highlighted the importance of FOXP3 in Alzheimer's disease, in with chronic inflammation leads to the development of myeloid plaques. This inflammation is caused by a loss of Foxp3 + regulatory T cells (Tregs). It would be interesting to investigate whether FOXP3 modulation plays a role in Alzheimer's disease, as it is the case with FOXO1 and FOXO3a. So FOX-miRNA modulation is involved in the progression of Alzheimer's disease. (Lau et al., 2013). This study „Alteration of the microRNA network during the progression of Alzheimer's disease“ observed the hippocampal miRNAs dysregulation of AD-patients. In them miR-132-3p expression on chromosome 17 was altered in both hemispheres. In AD stages III and IV it was severely decreased (41 persons with late-stage AD were compared to 23 healthy volunteers). This dysregulation was mainly observed in tau hyperphosphorylated neurons. This miRNA may affect both the TAU and the transcription factor FOXO1, whose expression is increased in the LOAD hippocampus. According to Wong et al. (2013), miR-132-3p also regulates FOXO3a, which in turn activates pro-apoptotic genes and is overexpressed in LOAD

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