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Differential regulation of autophagy by STAU1 in alveolar rhabdomyosarcoma and non‐transformed skeletal muscle cells

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Abstract

Purpose

Recent work has highlighted the therapeutic potential of targeting autophagy to modulate cell survival in a variety of diseases including cancer. Recently, we found that the RNA-binding protein Staufen1 (STAU1) is highly expressed in alveolar rhabdomyosarcoma (ARMS) and that this abnormal expression promotes tumorigenesis. Here, we asked whether STAU1 is involved in the regulation of autophagy in ARMS cells.

Methods

We assessed the impact of STAU1 expression modulation in ARMS cell lines (RH30 and RH41), non-transformed skeletal muscle cells (C2C12) and STAU1-transgenic mice using complementary techniques.

Results

We found that STAU1 silencing reduces autophagy in the ARMS cell lines RH30 and RH41, while increasing their apoptosis. Mechanistically, this inhibitory effect was found to be caused by a direct negative impact of STAU1 depletion on the stability of Beclin-1 (BECN1) and ATG16L1 mRNAs, as well as by an indirect inhibition of JNK signaling via increased expression of Dual specificity phosphatase 8 (DUSP8). Pharmacological activation of JNK or expression silencing of DUSP8 was sufficient to restore autophagy in STAU1-depleted cells. By contrast, we found that STAU1 downregulation in non-transformed skeletal muscle cells activates autophagy in a mTOR-dependent manner, without promoting apoptosis. A similar effect was observed in skeletal muscles obtained from STAU1-overexpressing transgenic mice.

Conclusions

Together, our data indicate an effect of STAU1 on autophagy regulation in ARMS cells and its differential role in non-transformed skeletal muscle cells. Our findings suggest a cancer-specific potential of targeting STAU1 for the treatment of ARMS.

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Data availability

The data supporting the findings are available within the article and its supplementary materials. Additional supporting data and material are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

STAU1:

Staufen1

ARMS:

Alveolar Rhabdomyosarcoma

BECN1:

Beclin-1

DUSP8:

Dual specificity phosphatase 8

ERMS:

Embryonal Rhabdomyosarcoma

RBPs:

RNA-binding proteins

GAPDH:

3-phosphate dehydrogenase

LC3:

Microtubule-associated protein 1 light chain 3

BafA1:

Bafilomycin A1

CQ:

Chloroquine

RIP:

RNA immunoprecipitation

p-mTOR:

phospho-mTOR

p-AKT:

phospho-AKT

p-JNK:

phospho-JNK

TA:

Tibialis Anterior

TG:

Transgenic

WT:

Wildtype

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Acknowledgements

We thank Dr. Pantic (University of Padua, Italy) for providing HSMM-C2 and HSMM-C3 cell lines. This work was supported by grants from the Cancer Research Society (CRS).

Funding

This study was supported by grants from the Cancer Research Society (CRS).

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada

    Shekoufeh Almasi, Tara E. Crawford Parks, Aymeric Ravel-Chapuis, Alex MacKenzie, Jocelyn Côté, Kyle N. Cowan & Bernard J. Jasmin

  2. The Eric J. Poulin Centre for Neuromuscular Diseases, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Shekoufeh Almasi, Tara E. Crawford Parks, Aymeric Ravel-Chapuis, Alex MacKenzie, Jocelyn Côté & Bernard J. Jasmin

  3. Division of Endocrinology, Department of Paediatric, CHEO, University of Ottawa, Ottawa, ON, Canada

    Alex MacKenzie

  4. Division of Paediatric Surgery, Department of Surgery, CHEO, University of Ottawa, Ottawa, ON, Canada

    Kyle N. Cowan

  5. Molecular Biomedicine Program, CHEO, Ottawa, ON, Canada

    Kyle N. Cowan

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  1. Shekoufeh Almasi
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Shekoufeh Almasi. The first draft of the manuscript was written by Shekoufeh Almasi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bernard J. Jasmin.

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All animal experimental protocols were approved by the University of Ottawa Institutional Animal Care Committee and were in accordance with the Canadian Council of Animal Care guidelines.

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Almasi, S., Crawford Parks, T.E., Ravel-Chapuis, A. et al. Differential regulation of autophagy by STAU1 in alveolar rhabdomyosarcoma and non‐transformed skeletal muscle cells. Cell Oncol. 44, 851–870 (2021). https://doi.org/10.1007/s13402-021-00607-y

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  • DOI: https://doi.org/10.1007/s13402-021-00607-y

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