RNA-binding protein complex LIN28/MSI2 enhances cancer stem cell-like properties by modulating Hippo-YAP1 signaling and independently of Let-7

Hailin Zou,Peng Li,Yun Wang,Yuhong Liu,Juan Luo,Yibo Guo,Liang Deng

doi:10.1038/s41388-022-02198-w

Abstract

The RNA binding protein LIN28 directly modulates the stability and translation of target mRNAs independently of Let-7; however, the key downstream targets of LIN28 in this process are largely unknown. Here, we revealed that Hippo signaling effector YAP1 functioned as a key downstream regulator of LIN28 to modulate the cancer stem cell (CSC)-like properties and tumor progressions in triple negative breast cancer (TNBC). LIN28 was overexpressed in BC tissues and cell lines, and significantly correlated with poorer overall survivals in patients. Ectopic LIN28 expression enhanced, while knockdown of LIN28A inhibited the CSC-like properties, cell growth and invasive phenotypes of TNBC cells in vitro and in vivo. Transcriptome analysis demonstrated LIN28 overexpression significantly induced the expressions of YAP1 downstream genes, while reduced the transcripts of YAP1 upstream kinases, such as MST1/2 and LATS1/2, and knockdown of LIN28A exhibited the opposite effects. Furthermore, constitutive activation of YAP1 in LIN28 knockdown TNBC cells could rescue the cell growth and invasive phenotypes in vitro and in vivo. Mechanistically, instead of the dependence of Let-7, LIN28 recruited RNA binding protein MSI2 in a manner dependent on the LIN28 CSD domain and MSI2 RRM domain, to directly induce the mRNA decay of YAP1 upstream kinases, leading to the inhibition of Hippo pathway and activation of YAP1, which eventually gave rise to increased CSC populations, enhanced tumor cell growth and invasive phenotypes. Accordingly, co-upregulations of LIN28 and MSI2 in TNBC tissues were strongly associated with YAP1 protein level and tumor malignance. Taken together, our findings unravel a novel LIN28/MSI2-YAP1 regulatory axis to induce the CSC-like properties, tumor growth and metastasis, independently of Let-7, which may serve as a potential therapeutic strategy for the treatment of a subset of TNBC with LIN28 overexpression.

Highlights

cancer stem cell (CSC) are a small population of cells with properties of self-renewal and multipotency, which are believed to contribute to the development and overall aggressiveness of the recurrent or metastatic lesions [1, 2]
The results revealed that LIN28A/B expression was significantly upregulated in primary BCs, and the BC patients with LIN28A/B high expression suffered shorter overall survival (Fig. S1A, B)
We found LIN28A was mainly localized in both cytoplasm and nuclear as previously described, and its expression level was significantly higher in BC tissues based on the IHC score (Fig. 1A)

Summary

Introduction

CSCs are a small population of cells with properties of self-renewal and multipotency, which are believed to contribute to the development and overall aggressiveness of the recurrent or metastatic lesions [1, 2]. TNBC is the most aggressive BC subtypes with no effective standard therapy [3, 4]. Targeting CSC regulation might be a promising strategy for curing the TNBC. The RNA-binding protein LIN28 is initially identified as a developmental timing regulator in C.elegans, and it has two homologs LIN28A/B in mammals [7, 8]. Accumulating studies have revealed that LIN28 is a master regulator for controlling the pluripotency of stem cells, and the stemness of cancer cells [9,10,11,12]. LIN28 combined with a cocktail of core reprogramming factors, like OCT4 and SOX2 was able to promote both mouse and human iPSC reprogramming efficiency by upregulating numerous cell-cycle and cell growth regulators [13, 14]

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Results

Conclusion