Hypoxia induces an endometrial cancer stem-like cell phenotype via HIF-dependent demethylation of SOX2 mRNA

Guofang Chen,Kai Wang,Binya Liu,Shasha Yin,Mengfei Wang,Yu’E Guo,Shuangdi Li,Xiaoping Wan

doi:10.1038/s41389-020-00265-z

Guofang Chen, Kai Wang + Show 6 more

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https://doi.org/10.1038/s41389-020-00265-z

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Journal: Oncogenesis	Publication Date: Sep 1, 2020
Citations: 58	License type: open-access

Affiliation: Shanghai First Maternity and Infant Hospital

Abstract

Endometrial cancer stem cells (ECSCs) are stem-like cells endowed with self-renewal and differentiation abilities, and these cells are essential for cancer progression in endometrial cancer (EC). As hallmarks of the tumour microenvironment (TME), hypoxia and hypoxia-inducing factors (HIFs) give rise to the dysregulation of tumour stemness genes, such as SOX2. Against this backdrop, we investigated the regulatory mechanisms regulated by HIFs and SOX2 in ECSCs during EC development. Here, ECSCs isolated from EC cell lines and tissues were found to express stemness genes (CD133 and aldehyde dehydrogenase, ALDH1) following the induction of their ECSC expansion. Notably, m6A methylation of RNA and HIF-1α/2α-dependent AlkB homologue 5 (ALKBH5) participate in the regulation of HIFs and SOX2 in EC, as confirmed by the observations that mRNA levels of m6A demethylases and ALKBH5 significantly increase under hypoxic conditions in ECSCs. Moreover, hypoxia and high ALKBH5 levels restore the stem-like state of differentiated ECSCs and increase the ECSC-like phenotype, whereas the knockdown of HIFs or ALKBH5 significantly reduces their tumour initiation capacity. In addition, our findings validate the role of ALKBH5 in promoting SOX2 transcription via mRNA demethylation, thereby maintaining the stem-like state and tumorigenicity potential of ECSCs. In conclusion, these observations demonstrate a critical role for m6A methylation-mediated regulation of the HIF-ALKBH5-SOX2 axis during ECSC expansion in hypoxic TMEs.

Highlights

Endometrial carcinoma (EC) is the most frequent gynaecological cancer in women, with an estimated 65,620 new cases and 12,590 deaths in the U.S in 20201–3
To explore the molecular mechanisms that regulate m6A demethylation of SOX2 in Endometrial cancer stem cells (ECSCs), we investigated the function of hypoxia-inducing factors (HIFs) and SOX2 in ECSCs and demonstrated that AlkB homologue 5 (ALKBH5) was induced under hypoxic conditions, wherein it decreased m6A methylation of SOX2 messenger RNA (mRNA) and changed the fate of
It is quite remarkable that ECSCs undergo differentiation in vitro, and the maintenance of the ECSC phenotype relies on supplementation with many growth factors

Summary

Introduction

Endometrial carcinoma (EC) is the most frequent gynaecological cancer in women, with an estimated 65,620 new cases and 12,590 deaths in the U.S in 20201–3. As the fourth most common cancer in women in terms of new cases, EC incidences have been rapidly increasing over the last 10 years as a consequence of a higher overall prevalence of obesity and metabolic syndromes[4,5]. CSCs can be induced to maintain a stem-like state or to differentiate and express specific surface markers (i.e., CD24, CD34, CD38, CD44, CD117, CD55, CD133 and aldehyde dehydrogenase, ALDH1)[7,8,9], among which CD44, CD55, CD117, CD133 and ALDH1 are reported to be enriched in ECSCs6. The role of ECSCs is controversial, and no universal markers specific for ECSCs have been confirmed[10,11,12]

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