CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance

Abstract

Radiotherapy is a mainstay for treatment of many human cancer types, including head and neck squamous cell carcinoma (HNSCC). Thereby, it is clinically very relevant to understand the mechanisms determining radioresistance. Here, we identify CIP2A as an Oct4 target gene and provide evidence that they co-operate in radioresistance. Oct4 positively regulates CIP2A expression both in testicular cancer cell lines as well as in embryonic stem cells. To expand the relevance of these findings we show that Oct4 and CIP2A are co-expressed in CD24 positive side-population of patient-derived HNSCC cell lines. Most importantly, all Oct4 positive HNSCC patient samples were CIP2A positive and this double positivity was linked to poor differentiation level, and predicted for decreased patient survival among radiotherapy treated HNSCC patients. Oct4 and CIP2A expression was also linked with increased aggressiveness and radioresistancy in HNSCC cell lines. Together we demonstrate that CIP2A is a novel Oct4 target gene in stem cells and in human cancer cell lines. Clinically these results suggest that diagnostic evaluation of HNSCC tumors for Oct4 or Oct4/CIP2A positivity might help to predict HNSCC tumor radioresistancy. These results also identify both Oct4 and CIP2A as potential targets for radiosensitation.

CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

“…This suggested that similar to bona-fide stem cell factor Oct4, also CIP2A is expressed in radioresistant population of testicular cells. Further, we showed that Oct4 is an upstream regulator of CIP2A expression in testicular cancer cell lines and embryonic stem cell model, and consistent with the role of CIP2A in regulating MYC, Oct4 depletion led to inhibition of MYC serine 62 phosphorylation [21]. CIP2A and Oct4 were also shown to be coexpressed in testicular cancer patient samples.…”

“…These conclusions are further supported by recent demonstration that CIP2A is expressed together with its target MYC in crypts of mouse intestinal cells, and that similar to MYC, CIP2A is required for efficient intestinal regeneration in response to both irradiation as well as DNA damaging therapy cisplatin [27]. Importantly, both Oct4-driven CIP2A expression in testicular cancer cells [21], and CIP2A expression in regenerating irradiated mouse intestines [27], promoted expression of oncogenic serine 62 phosphorylated form of MYC. Furthermore, CIP2A expression was shown to define cancer cell response to checkpoint kinase Chk1 inhibitors used in clinical cancer trials [16].…”

“…In our recent study [21], we aimed to elucidate the link between CIP2A and other stem cell markers such as octamer-binding transcription factor 4 (Oct4). Oct4 plays a significant role in the stemness regulation of embryonic stem cells and testicular stem cells, and has previously been shown to confer radioresistance and cancer stem cell phenotype in human cancer [8,22].…”

“…Next, we studied similar mechanisms in patient-derived HNSCC cell lines, and showed, that CIP2A and Oct4 expression levels significantly correlated with each other [21]. To study putative HNSCC cancer stem cells, we isolated CD44 and CD24 double positive cells using FACS.…”

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

“…This neoplastic progression in cancer cells causes an accumulation of genetic and epigenetic alterations by multiple DNA mutations and clonal selection. These changes cause cancer cells to return to and neck (7), and prostate (8) cancers. They are relevant to tumorigenicity, metastasis (9) and radioresistance (7).…”