2. Academic Validation
  3. RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway

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

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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