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Cellular and Molecular Biology

RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway

British Journal of Cancer volume 124, pages 2004–2016 (2021)Cite this article

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A Correction to this article was published on 07 May 2021

This article has been updated

Abstract

Background

Chemoresistance is one of the major factors for treatment failure in OSCC. Identifying key resistance triggering molecules will be useful strategy for developing novel treatment methods.

Methods

To identify the causative factors of chemoresistance, we performed RNA sequencing and global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin-resistance patterns.

Results

From the common set of dysregulated genes from both the analysis, RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is upregulated in chemotherapy-non-responder tumours as compared to chemotherapy-responder tumours. Genetic (knockout) or pharmacological (Radezolid, represses expression of RRBP1) inhibition of RRBP1 restores cisplatin-mediated cell death in chemo-resistant OSCC. Mechanistically, RRBP1 regulates Yes-associated protein1 (YAP1), a key protein in the Hippo pathway to induce chemoresistance. The PDC xenograft data suggests that knockout of RRBP1 induces cisplatin-mediated cell death and facilitates a significant reduction of tumour burden.

Conclusion

Overall, our data suggests that (I) RRBP1 is a major driver of cisplatin-resistance in OSCC, (II) RRBP1 regulates YAP1 expression to mediate cisplatin-resistance, (III) Radezolid represses RRBP1 expression and (IV) targeting RRBP1 reverses cisplatin-induced chemoresistance in advanced OSCC.

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Fig. 1: Global proteomics and transcriptomics data revealed RRBP1 is upregulated in OSCC chemo-resistant cells.
Fig. 2: RRBP1 knockout sensitised chemo-resistant resistant cells to cisplatin.
Fig. 3: RRBP1 regulates YAP1 in chemo-resistant OSCC.
Fig. 4: Radezolid represses RRBP1 protein expression and regulate YAP1 target genes in chemo-resistant OSCC.
Fig. 5: Radezolid (oxazolidinone group antibiotic) restored cisplatin-induced cell death in chemo-resistant OSCC.
Fig. 6: Knockout of RRBP1 restores cisplatin-induced cell death in chemo-resistant xenografts.

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Acknowledgements

O.S. is a UGC-SRF, S.M. is UGC-JRF, P.M. is CSIR SRF. S.R.K. and F.P. received fellowship from Department of Biotechnology. K.C.M. received institutional fellowship.

Author information

Authors and Affiliations

  1. Institute of Life Sciences, Bhubaneswar, Odisha, India

    Omprakash Shriwas, Sibasish Mohanty, Pallavi Mohapatra, Sugandh Kumar, Krushna Chandra Murmu, Anshuman Dixit, Punit Prasad & Rupesh Dash

  2. Manipal Academy of Higher Education, Manipal, Karnataka, India

    Omprakash Shriwas

  3. Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India

    Rakesh Arya, Sandeep Rai Kaushik, Falak Pahwa & Ranjan K. Nanda

  4. Regional Centre for Biotechnology, Faridabad, India

    Sibasish Mohanty & Pallavi Mohapatra

  5. Dept of Oral & Maxillofacial Pathology, SCB Dental College, Cuttack, Odisha, India

    Rachna Rath

  6. Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India

    Saroj Kumar Das Majumdar

  7. Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India

    Dillip Kumar Muduly

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Contributions

O.S., S.M., R.A., P.M., S.R.K., F.P., S.K., P.P. and K.C.M. performed experiments, and analysed the data, under the direction of R.D. and R.K.N. R.R., D.K.M., A.D. and S.K.M. performed part of experiments. O.S. and R.D. designed experiments and supervised the study. O.S., R.D. and R.K.N. wrote the manuscript. All authors approved the final version.

Corresponding authors

Correspondence to Ranjan K. Nanda or Rupesh Dash.

Ethics declarations

Ethics approval and consent to participate

This study was approved by Human Ethics committees (HEC) of Institute of Life Sciences, (84/HEC/18) and All India Institute of Medical Sciences (AIIMS), (T/EMF/Surg.Onco/19/03). The animal-related experiments were approved by Institutional Animal Ethics Committee of Institute of Life Sciences, (ILS/IAEC-147-AH/FEB-19).

Data availability

All the mass spectrometry data files (. raw and. mgf) with result files were deposited in the ProteomeXchange Consortium (PXD0016977) and all the RNA-seq data file were deposited in ArrayExpress (E-MTAB-9697).

Competing interests

The authors declare no competing interests.

Funding information

Grant support: This work is supported by Institute of Life Sciences, Bhubaneswar intramural support, ICMR (5/13/9/2019-NCD-III) and DBT BT/INF/22/SP28293/2018 (for imaging facility). Core support from International Centre for Genetic Engineering and Biotechnology to R.K.N. is highly acknowledged.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: During the proof process the authors unfortunately removed of one the co-corresponding authors. The correct version should read: Correspondence: Rupesh Dash (rupesh.dash@gmail.com) or Ranjan K. Nanda (HYPERLINK “mailto:ranjan@icgeb.res.in” ranjan@icgeb.res.in).

Supplementary information

Supplementary Fig 1: Characterization of sensitive, early and late OSCC cisplatin-resistant lines

Supplementary Fig 2: PCA plot and fragmentation pattern of the RRBP1 protein

41416_2021_1336_MOESM3_ESM.tif

Supplementary figure 3: The confirmation of RRBP1 KO in OSCC Chemoresistance cell line done by using GeneArt®Genomic Cleavage Detection (GCD) Kit (Life technology) with PCR primers listed in supplem

Supplementary Figure 4: Overexpression of RRBP1 in human OSCC lines results in development of cisplatin resistance

Supplementary Fig 5: PDC and CAF isolation from primary chemotherapy non-responder tumor

Supplementary Figure 6: RNA Sequencing revealed YAP1 target genes modulated by RRBP1.

Supplementary Fig 7: Characterisation of RRBP1 knockdown in H357CisR cells

Supplementary Figure 8: Constitutive overexpression of s-127 rescue the resistance property in sensitive cells

Supplementary Tables 1

Supplementary Tables 2

Supplementary Tables 3

Supplementary Table 4

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Shriwas, O., Arya, R., Mohanty, S. et al. RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway. Br J Cancer 124, 2004–2016 (2021). https://doi.org/10.1038/s41416-021-01336-7

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