FoxO transcription factors in cancer metabolism

Abstract

FoxO transcription factors serve as the central regulator of cellular homeostasis and are tumor suppressors in human cancers. Recent studies have revealed that, besides their classic functions in promoting cell death and inducing cell cycle arrest, FoxOs also regulate cancer metabolism, an emerging hallmark of cancer. In this review, we summarize the regulatory mechanisms employed to control FoxO activities in the context of cancer biology, and discuss FoxO function in metabolism reprogramming in cancer and interaction with other key cancer metabolism pathways. A deeper understanding of FoxOs in cancer metabolism may reveal novel therapeutic opportunities in cancer treatment.

Keywords: Cancer metabolism; FoxO; Myc; Tumor suppression; mTOR.

Figure 1. FoxO regulation by growth factor and stress signaling

Growth factors inhibit FoxOs whereas stress signaling generally activates FoxOs. FoxOs are modulated at several mechanistic levels as indicated.

Figure 2. FoxO regulation by post-translational modifications

Multiple pathways converge to regulate FoxO activity. Growth factor signaling inhibits FoxO activity by promoting AKT activation. AKT-mediated inactivation of FoxOs is antagonized by stress-induced FoxO activation through various stress-induced kinases. FoxO activity is also modulated by a plethora of other kinases in response to particular stimuli such as DNA damage. Other post-translational modifications such as ubiquitylation, acetylation and methylation also regulate FoxO activity.

Figure 3. Role of FoxO TFs in cancer biology

(A) FoxOs mainly function as tumor suppressors, and inhibit tumor development through repressing various hallmarks of cancer. (B) In certain contexts, FoxOs can also promote tumor growth by maintaining cancer stem cells, inducing drug resistance, and reactivating the PI3K-AKT pathway.

Figure 4. FoxOs modulate cancer metabolism via multiple mechanisms

FoxOs can either promote or inhibit various metabolism processes in cancer cells as indicated.

Figure 5. FoxO crosstalk with other cancer metabolism pathways

(A) FoxOs negatively regulate mTORC1 by inducing the expression of BNIP3, Sestrins, and TSC1, which inhibit mTORC1. Reciprocally, mTORC1 can promote FoxO activation by inhibiting the PI3K-AKT signaling via negative feedback loop. While mTORC2 inhibit FoxOs through AKT, FoxOs can also promote mTORC2 activation through upregulating Rictor expression. (B) The reciprocal antagonism between Myc and FoxOs. FoxOs inhibit Myc through multiple mechanisms as indicated. (C) FoxOs promote autophagy through both transcriptional dependent and independent mechanisms.