Developmental Gene PAX9 Turns the Body’s Recycling System Into a Cancer Cell Killer

A gene best known for shaping teeth and the palate may hold one of the most unexpected keys yet to treating oral cancer. New research published in the British Journal of Cancer reveals that PAX9, a transcription factor long associated with craniofacial development, acts as a tumour suppressor in oral squamous cell carcinoma by switching on autophagy so aggressively that the recycling process becomes lethal to the cancer cell itself. The study, led by Chandra Sekhar Bhol and Sujit Kumar Bhutia of the National Institute of Technology Rourkela, with collaborators including autophagy pioneer Daniel J. Klionsky of the University of Michigan, Peter E. Lobie and Vijay Pandey of Tsinghua University, Gautam Sethi of the National University of Singapore and Shankargouda Patil of Roseman University, paints a striking picture of a developmental gene re-deployed as a molecular executioner.

Autophagy occupies a paradoxical place in cancer biology. In established tumours, the self-digestion pathway often helps malignant cells survive chemotherapy, starvation and other stresses by breaking down damaged components and recycling their building blocks. Many cancers guard this survival mechanism jealously. The new work flips that logic: when PAX9 is present in oral cancer cells, it drives autophagy so hard and so persistently that the process crosses a threshold from protective to destructive, a phenomenon researchers call lethal autophagy.

The mechanism at the heart of this effect is transcriptional. PAX9 is a DNA-binding protein, and the team found that its ability to kill cancer cells depends entirely on that function. When the researchers introduced the wild-type gene into oral cancer cells, expression of autophagy-related genes rose, lysosomal function intensified, and autophagic flux — the complete flow of cellular cargo through autophagosomes and into lysosomes for degradation — accelerated markedly. The cells responded by forming fewer orospheres, structures that reflect tumour-initiating capacity, and by undergoing apoptosis.

To prove the transcription factor’s role directly, the team engineered two point mutations in the PAX9 protein, L27P and I29T, which sit in the paired DNA-binding domain. Both mutations blocked the autophagy response and restored cell viability, showing that without PAX9’s ability to engage its target genes, the lethal cascade never begins. The result is technically elegant: it separates PAX9’s transcriptional activity from any indirect protein-level effects and establishes the gene’s antitumour action as strictly transcription-dependent.

The most consequential discovery, however, concerns what PAX9-driven autophagy chooses to digest. The researchers found that epidermal growth factor receptor, EGFR, is degraded through the autophagy-lysosome route in PAX9-expressing cells. EGFR is one of the most important growth drivers in head and neck cancer; amplification of its gene copy number is linked to poor prognosis, and EGFR-targeting drugs are standard components of oral cancer therapy. By funneling EGFR into the lysosomal shredder, PAX9 simultaneously strips cancer cells of a central survival signal and primes them for death.

This finding carries immediate therapeutic weight. Restoring PAX9 activity in tumours could, in principle, remove EGFR from the cancer cell’s toolkit through an entirely different route than antibody or small-molecule blockade, and the study showed that PAX9 expression sensitised cells to cisplatin, a mainstay chemotherapy drug. In a xenograft model in nude mice, PAX9 overexpression inhibited tumour growth and enhanced cisplatin sensitivity, providing in vivo support for the idea that this developmental gene could complement existing treatments rather than replace them.

The clinical corollary is equally telling. When the team examined human oral cancer tissue samples, PAX9 expression dropped as tumour grade increased, and the same decline appeared in a DMBA-induced hamster model of oral carcinogenesis. In vitro, exposure to carcinogens reduced PAX9 levels while raising DNMT1, the enzyme responsible for maintaining DNA methylation patterns. That pattern suggests the gene is silenced epigenetically during malignant transformation, a hypothesis consistent with the group’s earlier work showing that reactivating PAX9 by inhibiting DNA methyltransferases triggers antitumour effects in oral squamous cell carcinoma. Related PAX family members, including PAX1 and PAX4, have also been linked to tumour suppression and methylation-based silencing in other cancers, hinting at a broader family-level theme.

The study also contributes to a growing literature on the transcriptional regulation of autophagy. Classic regulators such as TFEB, which links lysosomal biogenesis to autophagy, and FOXO factors have dominated that field; PAX9 now joins a select group of transcription factors capable of dialling autophagy into the lethal range. Earlier work on dendrogenin A and other ligand-dependent transcriptional inducers of lethal autophagy suggested the concept had therapeutic potential, but identifying a specific developmental transcription factor that naturally performs this function in oral tissue gives the idea a concrete molecular handle.

Translating these findings into the clinic will require overcoming the challenge of reactivating a silenced gene in tumour cells. DNA methyltransferase inhibitors already exist and are approved for haematological malignancies, and the current results suggest they could one day be paired with autophagy or EGFR-targeting strategies in oral cancer. Because PAX9 loss appears to track with tumour grade, the protein may also serve as a biomarker indicating which patients would benefit from therapies designed to restore or mimic its function.

For a gene whose canonical job is to build the palate and pattern the dentition of the developing embryo, PAX9’s second career as an executioner of oral cancer cells is a vivid reminder that developmental biology and oncology share far more machinery than is often appreciated. The authors note that funding came from the Indian Council of Medical Research, the National Key R&D Program of China, Guangdong and Shenzhen science programs, Tsinghua Shenzhen International Graduate School and the US National Institutes of Health, underscoring the international scope of the effort. If the transcriptional circuit the team mapped can be pharmacologically engaged in patients, the humble tooth-development gene may prove to be one of oral cancer’s most surprising vulnerabilities.

Subject of Research: PAX9-mediated lethal autophagy and EGFR degradation as a tumour-suppressive mechanism in oral squamous cell carcinoma

Article Title: PAX9 activates autophagy through a transcription-dependent mechanism, promoting EGFR degradation to restrict cell survival in oral cancer

Article References: Bhol, C. S., Kar, R. K., Mishra, S. R., Mishra, P., Mahapatra, K. K., Zhang, X., Patra, S. K., Patil, S., Sethi, G., Klionsky, D. J., Lobie, P. E., Pandey, V., & Bhutia, S. K. (2026). PAX9 activates autophagy through a transcription-dependent mechanism, promoting EGFR degradation to restrict cell survival in oral cancer. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03608-6

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03608-6

Keywords: PAX9, oral cancer, autophagy, EGFR, lethal autophagy, tumour suppressor, transcription factor, lysosome, cisplatin, chemosensitisation, oral squamous cell carcinoma, DNA methylation