TY - JOUR
T1 - Genome-wide siRNA screens identify RBBP9 function as a potential target in Fanconi anaemia-deficient head-and-neck squamous cell carcinoma
AU - Pai, Govind
AU - Roohollahi, Khashayar
AU - Rockx, Davy
AU - de Jong, Yvonne
AU - Stoepker, Chantal
AU - Pennings, Charlotte
AU - Rooimans, Martin
AU - Vriend, Lianne
AU - Piersma, Sander
AU - Jimenez, Connie R.
AU - de Menezes, Renee X.
AU - van Beusechem, Victor W.
AU - Brakenhoff, Ruud H.
AU - te Riele, Hein
AU - Wolthuis, Rob M. F.
AU - Dorsman, Josephine C.
N1 - Funding Information:
JdW is dearly missed and his contribution to this project and our team is fondly remembered. We thank former members of the Oncogenetics lab for their assistance with optimisation and performing siRNA screens. We thank Mohamad Amr Zaini for his helpful discussions and inputs to the coIP experiments. We acknowledge support from Ida van der Meulen, RNAi screening facility, Department of Medical Oncology, Amsterdam UMC for help with setting up the genome-wide screens. We thank Prof. Dr. Mario van der Stelt, Professor of Molecular Physiology, Leiden Institute of Chemistry, for fruitful discussions on the enzymology of RBBP9. This study was supported by a KWF research grant (VU 2013-5983) awarded to (late) Johan de Winter (JdW), RB, and VvB. An NWO middelgroot grant (91116017) awarded to CJ supported the mass spectrometry infrastructure of The Oncoproteomics Laboratory.
Funding Information:
JdW is dearly missed and his contribution to this project and our team is fondly remembered. We thank former members of the Oncogenetics lab for their assistance with optimisation and performing siRNA screens. We thank Mohamad Amr Zaini for his helpful discussions and inputs to the coIP experiments. We acknowledge support from Ida van der Meulen, RNAi screening facility, Department of Medical Oncology, Amsterdam UMC for help with setting up the genome-wide screens. We thank Prof. Dr. Mario van der Stelt, Professor of Molecular Physiology, Leiden Institute of Chemistry, for fruitful discussions on the enzymology of RBBP9. This study was supported by a KWF research grant (VU 2013-5983) awarded to (late) Johan de Winter (JdW), RB, and VvB. An NWO middelgroot grant (91116017) awarded to CJ supported the mass spectrometry infrastructure of The Oncoproteomics Laboratory.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity.
AB - Fanconi anaemia (FA) is a rare chromosomal-instability syndrome caused by mutations of any of the 22 known FA DNA-repair genes. FA individuals have an increased risk of head-and-neck squamous-cell-carcinomas (HNSCC), often fatal. Systemic intolerance to standard cisplatin-based protocols due to somatic-cell hypersensitivity underscores the urgent need to develop novel therapies. Here, we performed unbiased siRNA screens to unveil genetic interactions synthetic-lethal with FA-pathway deficiency in FA-patient HNSCC cell lines. We identified based on differential-lethality scores between FA-deficient and FA-proficient cells, next to common-essential genes such as PSMC1, PSMB2, and LAMTOR2, the otherwise non-essential RBBP9 gene. Accordingly, low dose of the FDA-approved RBBP9-targeting drug Emetine kills FA-HNSCC. Importantly both RBBP9-silencing as well as Emetine spared non-tumour FA cells. This study provides a minable genome-wide analyses of vulnerabilities to address treatment challenges in FA-HNSCC. Our investigation divulges a DNA-cross-link-repair independent lead, RBBP9, for targeted treatment of FA-HNSCCs without systemic toxicity.
KW - Cell Cycle Proteins/genetics
KW - DNA
KW - Emetine/therapeutic use
KW - Fanconi Anemia/genetics
KW - Genome-Wide Association Study
KW - Head and Neck Neoplasms
KW - Humans
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Neoplasm Proteins/genetics
KW - RNA, Small Interfering/genetics
KW - Squamous Cell Carcinoma of Head and Neck/genetics
UR - https://www.scopus.com/pages/publications/85146303563
U2 - 10.1038/s42003-022-04389-3
DO - 10.1038/s42003-022-04389-3
M3 - Article
C2 - 36639418
SN - 2399-3642
VL - 6
SP - 37
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 37
ER -
SDG 3 Good Health and Well-being