Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression.

Shiyi Yu,Sheng Qin,Lele Wu,Yan Liu,Jean Paul Thiery,Zhenghong Yu,Yuzhi Wang,Chenxi Wu,Xiuxiu Cai,Liming Chen,Fei Ma

doi:10.18632/oncotarget.3095

Abstract

Targeted therapies are considered to be the future of cancer treatment. However, the mechanism through which intracellular signaling pathways coordinate to modulate oncogenesis remains to be elucidated. In this study, we describe a novel crosstalk among ERK, AKT and Hippo-YAP pathways, with CD44 as an upstream regulator. High cell density leads to activation of ERK and AKT but inactivation of YAP in cancer cells. CD44 modulates cell proliferation and cell cycle but not apoptosis. The expression and activity of cell cycle genes were cooperatively regulated by ERK, AKT and Hippo-YAP signaling pathways through CD44-mediated mechanisms. In addition, CD44 depletion abrogates cancer stem cell properties of tumor initiating cells. Taken together, we described a paradigm where CD44 functions as an upstream regulator sensing the extracellular environment to modulate ERK, AKT and Hippo-YAP pathways which cooperatively control downstream gene expression to modulate cell contact inhibition of proliferation, cell cycle progression and maintenance of tumor initiating cells. Our current study provides valuable information to design targeted therapeutic strategies in cancers.

Highlights

Cancer remains a leading cause of morbidity and mortality in humans
We found a decrease in p-yes-associated protein (YAP) upon treatment with PD0325901 (Figure 1A & C) and, consistently, found that silencing extracellular signal-regulated kinase1/2 (ERK1/2) with siRNAs decreased p-YAP (Figure 1B & D)
We found that high cell density increased p-ERK1/2 without affecting total ERK1/2 levels (Figure 2A), indicating the activation of extracellular-signal-regulated kinase (ERK) pathway can be induced by high cell density. phosphorylation of AKT (p-AKT) levels were increased but this was concomitant with decreased total AKT levels (Figure 2B), which suggests that high cell density can induce the AKT pathway activation

Summary

Introduction

Cancer remains a leading cause of morbidity and mortality in humans. Usually viewed as an evolutionary process, cancer results from the accumulation of somatic mutations in the progeny of a normal cell, leading to a selective growth advantage in the mutated cells and uncontrolled proliferation[1, 2]. Research has characterized the cellular and molecular events that enable the malignant transformation of cells[3] and several pathways are implicated to play important roles in oncogenesis. These include the wellcharacterized extracellular-signal-regulated kinase (ERK) and AKT pathways and the newly emerging Hippo-YAP pathway. In HippoYAP pathway, YAP is a downstream target of a core kinase cassette that consists of mammalian STE20-like protein kinase 1/2 (MST1/2), large tumour suppressor 1/2 (LATS1/2), Salvador homologue 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B)[8].The Hippo-YAP pathway, an evolutionarily conserved pathway, plays fundamental roles in the control of different tissues during development and regeneration as well as in cancer development[8, 9]. The abnormal activation of YAP causes ectopic cell proliferation[8] and was reported to be associated with many cancer types[8, 9, 11, 13, 14]

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Conclusion