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

  • Br J Cancer. 2021 Jun;124(12):2004-2016. doi: 10.1038/s41416-021-01336-7.
Omprakash Shriwas  1  2 ,  Rakesh Arya  3 ,  Sibasish Mohanty  1  4 ,  Pallavi Mohapatra  1  4 ,  Sugandh Kumar  1 ,  Rachna Rath  5 ,  Sandeep Rai Kaushik  3 ,  Falak Pahwa  3 ,  Krushna Chandra Murmu  1 ,  Saroj Kumar Das Majumdar  6 ,  Dillip Kumar Muduly  7 ,  Anshuman Dixit  1 ,  Punit Prasad  1 ,  Ranjan K Nanda  8 ,  Rupesh Dash  9
Affiliations
  • 1. Institute of Life Sciences, Bhubaneswar, Odisha, India.
  • 2. Manipal Academy of Higher Education, Manipal, Karnataka, India.
  • 3. Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
  • 4. Regional Centre for Biotechnology, Faridabad, India.
  • 5. Dept of Oral & Maxillofacial Pathology, SCB Dental College, Cuttack, Odisha, India.
  • 6. Department of Radiotherapy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India.
  • 7. Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India.
  • 8. Translational Health Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. [email protected].
  • 9. Institute of Life Sciences, Bhubaneswar, Odisha, India. [email protected].
PMID: 33762722 DOI: 10.1038/s41416-021-01336-7
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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