Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L

• Published in: Oncogene 2021-06, Vol.40 (24), p.4214-4228
• Main Authors: Nathansen, Jacqueline, Lukiyanchuk, Vasyl, Hein, Linda, Stolte, Maya-Isabel, Borgmann, Kerstin, Löck, Steffen, Kurth, Ina, Baumann, Michael, Krause, Mechthild, Linge, Annett, Dubrovska, Anna
• Format: Article
• Language: English
• Subjects: 13/1; 38/23; 38/77; 38/89; 38/90; 45/23; 631/67/1536; 631/67/395; 631/67/71; 692/53/2422; 96/1; 96/109; 96/63; Adult; Aged; Apoptosis; Cancer; Care and treatment; Cell Biology; Cell cycle; Cell self-renewal; Cell survival; CHK1 protein; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA Damage - genetics; DNA Helicases - genetics; DNA repair; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Genetic regulation; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Health aspects; Homologous recombination; Homologous Recombination - genetics; Human Genetics; Humans; Internal Medicine; Invasiveness; Lethality; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Neoplastic Stem Cells - pathology; Nuclear Proteins - genetics; Oct-4 protein; Octamer Transcription Factor-3 - genetics; Oncology; Oncology, Experimental; Phenotypes; Physiological aspects; Poly(ADP-ribose) polymerase; Radiation therapy; Radiation Tolerance - genetics; Radioresistance; Radiosensitization; Radiotherapy; Recombinant proteins; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - pathology; Stem cells; Trans-Activators - genetics; Transcription factors; Tumors; Young Adult
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01842-1

Head and neck squamous cell carcinoma (HNSCC) is often being diagnosed at an advanced stage, conferring a poor prognosis. The probability of local tumor control after radiotherapy depends on the eradication of cancer stem cells (CSCs) with activated DNA repair. This study provides evidence that the CSC-related transcription factor Oct4 contributes to HNSCC radioresistance by regulating DNA damage response and the CSC phenotype. Knockdown of Oct4 A isoform reduced self-renewal capacity in HNSCC and led to partial tumor cell radiosensitization caused by transcriptional downregulation of the cell cycle checkpoint kinases CHK1 and WEE1 and homologous recombination (HR) repair genes PSMC3IP and RAD54L. Besides, PARP inhibition with Olaparib selectively radiosensitized Oct4 A knockout, but not wild-type HNSCC cells. This finding links Oct4 A to the HR-mediated DNA repair mechanisms. In turn, knockdown of PSMC3IP and RAD54L reduced the HNSCC self-renewal capacity and clonogenic cell survival after irradiation, suggesting the interplay between DNA repair and the CSC phenotype. Similar to the effect of Oct4 knockdown, overexpression of Oct4 also resulted in significant HNSCC radiosensitization and increased DNA damage, suggesting that Oct4-dependent regulation of DNA repair depends on its fine-tuned expression. In line with this observation, HNSCC patients with high and low nuclear Oct4 expression at the invasive tumor front exhibited better loco-regional tumor control after postoperative radio(chemo)therapy compared to the intermediate expression subgroup. Thus, we found that the Oct4-driven transcriptional program plays a critical role in regulating HNSCC radioresistance, and a combination of radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors.