SOX2 promotes hypoxia-induced breast cancer cell migration by inducing NEDD9 expression and subsequent activation of Rac1/HIF-1α signaling

Wang, Yueyuan; Bibi, Maria; Min, Pengxiang; Deng, Wenjie; Zhang, Yujie; Du, Jie

doi:10.1186/s11658-019-0180-y

Cited by 30 publications

(24 citation statements)

References 37 publications

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“…Recently, a SOX2 knockdown experiment shows that basal cell carcinoma migration is regulated by Akt signalling pathway [ 58 ]. In agreement, another recent study shows that hypoxia-induced breast cancer cell migration is regulated by SOX2 transcription factor [ 112 ].…”

Section: Deregulation Of Foxos In Cancer and Metastasissupporting

confidence: 87%

FOXO transcription factor family in cancer and metastasis

Jiramongkol

Lam

2020

Cancer Metastasis Rev

173

118

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Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.

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Section: Deregulation Of Foxos In Cancer and Metastasissupporting

confidence: 87%

FOXO transcription factor family in cancer and metastasis

Jiramongkol

Lam

2020

Cancer Metastasis Rev

173

118

View full text Add to dashboard Cite

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“…Since RAC1 is required for activation of HIF1α [ 36 – 38 ], and RAC1 is the best-characterized ubiquitylation target of the HACE1 E3 ligase [ 10 , 15 – 18 ], we wondered whether HACE1’s effects on HIF1α are mediated through RAC1. We found that RAC1 activation was higher under hypoxia than ambient conditions in HEK293 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner

et al. 2021

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Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1–/– mice in murine KRasG12D-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.

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“…In gastric cancer, SOX2 enhances HIF-1α promoter activity to regulate glucose metabolism 61 . Previous work on the crucial role of SOX2 in breast cancer cell migration showed that SOX2 upregulation in hypoxic conditions facilitated NEDD9 transcription and subsequent activation of HIF-1α expression 62 . This evidence extends our knowledge with regard to the diverse roles of SOX2 and HIFs in cancers.…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2020

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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.

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SOX2 promotes hypoxia-induced breast cancer cell migration by inducing NEDD9 expression and subsequent activation of Rac1/HIF-1α signaling

Cited by 30 publications

References 37 publications

FOXO transcription factor family in cancer and metastasis

FOXO transcription factor family in cancer and metastasis

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner

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

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