Lin28 and let-7 in cell metabolism and cancer

Abstract

Malignant cells exhibit major metabolic alterations. The regulatory gene networks that regulate metabolism and the impact of these alterations on overall cellular fitness deserve further exploration. The let-7 microRNAs and their antagonists, the Lin28 RNA-binding proteins, are well-known for controlling the timing of embryonic development. This pathway has recently been shown to regulate glucose metabolism in adult mice and to reprogram metabolism during tissue injury and repair. In addition, many lines of evidence have established that Lin28 is an oncogene that drives tumorigenesis in part by suppressing let-7. The metabolic underpinnings of this oncogenic program are just beginning to be uncovered. Here, we will review the current understanding of how Lin28 exerts regenerative and oncogenic effects through metabolic mechanisms.

Keywords: Lin28, let-7; cancer; metabolism; regeneration.

Figure 1

Reactivation of Lin28 reprograms cell metabolism to enhance tissue regeneration and promote cancer growth. (A) Reactivation of Lin28 in physiological condition in mouse tissues enhances regeneration by suppressing let-7, upregulating K-Ras expression and the insulin-PI3K-mTOR signaling, and more importantly upregulating the expression of metabolic machinery. These changes lead to enhanced glucose uptake, increased activity of both glycolysis and OxPhos, resulting in Lin28-positive cells having a much higher bioenergetic state; (B) Reactivation of Lin28 promotes growth of multiple cancer cell lines in part by suppressing let-7 and upregulating PDK1 protein expression. When let-7 expression is reduced, glucose uptake is enhanced. PDK1 is a negative regulator of OxPhos activity since it inhibits the conversion of pyruvate to acetyl-CoA. When PDK1 expression is enhanced by Lin28 overexpression and let-7 suppression, it promotes glycolysis and blocks OxPhos activity. Consequently, Lin28-positive cancer cells switch to aerobic glycolysis for glucose metabolism.