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

Abstract

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.

A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression

“…For example, overexpression of the redox effector factor (Ref-1), an enzyme activated in the base excision repair (BER) pathway, decreases ROS levels in cancer cells, resulting in enhanced cancer cell stemness [ 35 ]. Oct4, a stemness-associated transcription factor encoded by the POU5F1 gene, regulates the CSC phenotype and radioresistance by contributing to the HR-mediated DNA repair response [ 36 ]. Therefore, specific inhibition of DNA repair pathways could improve tumor response and clinical outcome in cancer patients by interfering with the signal transduction in CSCs.…”

San-Zhong-Kui-Jian-Tang Exerts Antitumor Effects Associated With Decreased Cell Proliferation and Metastasis by Targeting ERK and the Epithelial–Mesenchymal Transition Pathway in Oral Cavity Squamous Cell Carcinoma

“… 41 In addition, Oct-4, an important regulator of stemness in head and neck squamous carcinoma, and high Oct-4 expression and poor survival were found to be significantly correlated in patients with head and neck cancer. 42 The results herein demonstrated that SZKJT inhibited the expression of Oct-4. Furthermore, our results clearly show that the activity of SZKJT against oral cancer is mediated via ERK pathway and that SZKJT decreases EMT in OSCC.…”

Cancer Stem Cell DNA Enabled Real‐Time Genotyping with Self‐Functionalized Quantum Superstructures—Overcoming the Barriers of Noninvasive cfDNA Cancer Diagnostics

“…[60,62] OCT4 is known to promote the self-renewal of CSCs and participating in maintaining the stem characteristics of CSCs was chosen for this analysis. [61] SOX2 expression in human cancers has been widely investigated. The SOX2 overexpression is positively correlated to cancer stem cells.…”