Role of Forkhead Box Class O proteins in cancer progression and metastasis

Abstract

It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis.

5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

“…FoxOs are well‐known downstream effectors of the PI3K/AKT signaling . RNA sequencing also revealed that FoxO6 was one of the top decreased molecules in HCC cells with 5‐HT1D knockdown.…”

LncRNA ST3Gal6‐AS1/ST3Gal6 axis mediates colorectal cancer progression by regulating α‐2,3 sialylation via PI3K/Akt signaling

“…The regulatory role of the PI3K/Akt pathway in cancer development has received much attention. Foxo1 is a nuclear transcription protein with highly conserved DNA binding sites, and is the substrate of PI3K/Akt, which plays a negative role in insulin signal transduction . Foxo1 is well known to mediate apoptosis by activating the proapoptotic genes, such as FasL and Bim .…”

FOXO Transcription Factors Both Suppress and Support Breast Cancer Progression

“…FOXOs are putative tumor suppressors as combined loss of Foxo1, Foxo3, and Foxo4 in adult mice results in increased hematopoietic lineage-specific tumors and FOXO activation arrests the cell cycle and induces apoptosis or anoikis in multiple types of tumor cells (2)(3)(4)(5). Despite their tumor-suppressive roles, mutational loss of all FOXO alleles is statistically unlikely and has not been reported in cancer.…”

“…It has been suggested that FOXOs may also contribute to tumorigenesis, and a more active mutant form of FOXO1 has been reported in cancer (3,(5)(6)(7)(8)(9)(10). In addition, FOXOs have been implicated in a drug resistance signaling feedback loop that reestablishes RTK-PI3K-AKT signaling after pharmacologic inhibition of AKT/PKB (11)(12)(13).…”