FOXL2 and FOXA1 cooperatively assemble on the <i>TP53</i> promoter in alternative dimer configurations

Choi, Yuri; Lee, Seunghwa; Jin, Hanyong; Yoon, Hye‐Jin; Hahn, Yoonsoo; Bae, Jang–Ho; Lee, Hyung Ho

doi:10.1093/nar/gkac673

Cited by 6 publications

(4 citation statements)

References 83 publications

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“…Given the finding in our data and others of FOXL2 C134W positive tumors with diverse histology, we feel broader testing is justified. The involvement of FOXL2 gene mutations in cancer and the need for clinical testing is further supported by recent publications indicating a potential role of FOXL2 in cancer suppression, as FOXL2 is normally involved in the transcriptional activation of TP53 (17) and in stabilizing DNA double-strand break repair (18).…”

Section: Discussionmentioning

confidence: 87%

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

Wessman,

Fuentes,

Severin-Karlsson

et al. 2023

International Journal of Gynecological Pathology

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Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.

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Section: Discussionmentioning

confidence: 87%

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

Wessman,

Fuentes,

Severin-Karlsson

et al. 2023

International Journal of Gynecological Pathology

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“…However, the similar expression patterns of foxl2 and hsd17b1 raise the question of whether foxl2 might not regulate hsd17b1 . In fact, a recent study revealed that FOX proteins in the human genome, including FOXL2 , stimulate tumor suppressor TP53, acting as upstream regulators of this protein (Choi et al, 2022). Moreover, in porcine granulosa, TP53 positively regulates transcription and translation of Hsd17b1 (Yuan et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

hsd17b1 is a key gene for ovarian differentiation of the Siberian sturgeon

Lasalle,

Benech‐Correa,

Brunet

et al. 2024

Molecular Reproduction Devel

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This is the first work using gonads from undifferentiated, genetically‐sexed Siberian sturgeon describing expression changes in genes related to steroid synthesis and female and male sex differentiation. One factor identified as relevant for ovarian differentiation was the gene coding for the enzyme Hsd17b1, which converts estrone into estradiol‐17β. hsd17b1 was highly activated in female gonads at 2.5 months of age, around the onset of sex differentiation, preceding activation of two other genes involved in estrogen production (cyp19a1 and foxl2). hsd17b1 was also strongly repressed in males. Two known foxl2 paralogs are found in Siberian sturgeon—foxl2 and foxl2l—but only foxl2 appeared to be associated with ovarian differentiation. With regard to the male pathway, neither 11‐oxygenated androgens nor classic male genes (amh, dmrt1, sox9, and dhh) were found to be involved in male sex differentiation, leaving open the question of which genes participate in early male gonad development in this ancient fish. Taken together, these results indicate an estrogen‐dependence of female sex differentiation and 11‐oxygenated androgen‐independence of male sex differentiation.

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“…FOXA1 is a pioneer of epigenetic reprogramming in both stem cells and cancer cells and is involved in DNA repair complex formation and DNA demethylation [ 67 , 68 ]. Although both genes are known cancer drivers, the cooperative role of these two genes in cancer has largely not been fully elucidated until recently [ 69 ]. Nevertheless, the association between Hypo-MS4 and neoantigen load as well as the suppression of immune responses in the TIME further strengthened the relationship between FOXA1 activity and cancer immunity.…”

Section: Discussionmentioning

confidence: 99%

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

Qin,

Zhou,

Guo

et al. 2024

Genome Med

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Background Aberrant DNA methylation is a major characteristic of cancer genomes. It remains unclear which biological processes determine epigenetic reprogramming and how these processes influence the variants in the cancer methylome, which can further impact cancer phenotypes. Methods We performed pairwise permutations of 381,900 loci in 569 paired DNA methylation profiles of cancer tissue and matched normal tissue from The Cancer Genome Atlas (TCGA) and defined conserved differentially methylated positions (DMPs) based on the resulting null distribution. Then, we derived independent methylation signatures from 2,465 cancer-only methylation profiles from the TCGA and 241 cell line-based methylation profiles from the Genomics of Drug Sensitivity in Cancer (GDSC) cohort using nonnegative matrix factorization (NMF). We correlated DNA methylation signatures with various clinical and biological features, including age, survival, cancer stage, tumor immune microenvironment factors, and immunotherapy response. We inferred the determinant genes of these methylation signatures by integrating genomic and transcriptomic data and evaluated the impact of these signatures on cancer phenotypes in independent bulk and single-cell RNA/methylome cohorts. Results We identified 7,364 differentially methylated positions (2,969 Hyper-DMPs and 4,395 Hypo-DMPs) in nine cancer types from the TCGA. We subsequently retrieved three highly conserved, independent methylation signatures (Hyper-MS1, Hypo-MS1, and Hypo-MS4) from cancer tissues and cell lines based on these Hyper and Hypo-DMPs. Our data suggested that Hypo-MS4 activity predicts poor survival and is associated with immunotherapy response and distant tumor metastasis, and Hypo-MS4 activity is related to TP53 mutation and FOXA1 binding specificity. In addition, we demonstrated a correlation between the activities of Hypo-MS4 in cancer cells and the fractions of regulatory CD4 + T cells with the expression levels of immunological genes in the tumor immune microenvironment. Conclusions Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.

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FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations

Cited by 6 publications

References 83 publications

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology

hsd17b1 is a key gene for ovarian differentiation of the Siberian sturgeon

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

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