This study evaluated expression of the transcription factor PAX9 in human oral squamous cell carcinoma (OSCC) specimens and in a DMBA-induced hamster oral carcinogenesis model. The authors report decreased PAX9 expression in higher-grade human oral cancers and reduced levels in the DMBA model, indicating downregulation of PAX9 during oral carcinogenesis.
Using overexpression approaches, the investigators show that PAX9 activates autophagy via a transcription-dependent mechanism. The preview indicates that overexpressed PAX9 enhanced expression of multiple autophagy-related genes and associated signalling pathways. Details of the specific transcriptional targets, promoter interactions, or chromatin-level data were not reported in the preview accessible here.
Functional assays demonstrated that PAX9 overexpression increased lysosomal activity and promoted autophagosome-lysosome fusion in OSCC cells. The authors observed induction of autophagic flux when PAX9 was overexpressed, consistent with an increase in complete autophagy pathway activity rather than accumulation of autophagosomes alone.
A key consequence of PAX9-driven autophagy reported in the study is degradation of the epidermal growth factor receptor (EGFR). The authors show that autophagy activation by PAX9 leads to downregulation of EGFR protein levels, linking PAX9 activity to reduced signalling through a major tumour cell survival pathway in OSCC.
Point mutations at residues L27P and I29T in PAX9 were tested for functional effects. Both mutants blocked the ability of PAX9 to induce autophagy and thereby restored cell viability in OSCC models. These findings indicate that these residues are important for PAX9's autophagy-activating, tumour-suppressive activity.
The study reports that activation of autophagy by PAX9 triggered apoptosis in OSCC cells, an effect described as “lethal autophagy.” PAX9 overexpression inhibited in vitro measures of tumourigenicity, including orosphere formation, and decreased cell growth through apoptotic mechanisms.
In vivo, PAX9 overexpression enhanced sensitivity to cisplatin and inhibited tumour growth in xenograft experiments using nude mice. These results support a potential therapeutic role for restoring or augmenting PAX9 function to improve chemotherapy response in OSCC.
The authors examined the effects of carcinogen exposure in vitro and report that exposure reduced PAX9 expression while increasing DNMT1 levels. This pattern suggests that DNA methylation may contribute to PAX9 repression during oral carcinogenesis. The preview does not include detailed methylation mapping data or direct evidence of promoter methylation, only the observed inverse changes in PAX9 and DNMT1 following carcinogen exposure.
Decreased PAX9 expression in higher-grade human oral cancers as reported in this work is consistent with a tumour-suppressive role. The combination of reduced PAX9 in clinical specimens and in an animal carcinogenesis model, together with functional evidence that PAX9 activation promotes lethal autophagy and EGFR degradation, positions PAX9 as a candidate molecular regulator relevant to OSCC progression and therapy response.
The authors state that data supporting the findings are available from the corresponding author upon reasonable request, noting that some data may be restricted by privacy or ethical considerations. The accessible preview does not provide full methodological detail, raw datasets, or complete lists of transcriptional targets; those elements are contained in the full article and are not reported here.
Overall, the article presents evidence that PAX9 functions as a transcription-dependent activator of autophagy in OSCC, that this autophagy is linked to EGFR degradation and apoptosis, and that loss of PAX9 expression during carcinogenesis may be mediated in part by epigenetic mechanisms. These observations support further investigation of PAX9 as a potential tumour suppressor and therapeutic sensitiser in oral cancer.