Pancreatic cancer is a highly lethal malignancy and is anticipated to become the second-leading cause of cancer-related mortality by 20301. Due to its rapid progression, approximately 80% of patients with pancreatic cancer are diagnosed at an advanced stage. The 5-year survival rate is less than 10% across all stages, representing the lowest survival rate among cancers2. Despite strides in understanding and the application of novel targets, such as KRAS, BRCA1/2, and targeted therapies in clinical practice, their impact is limited, often resulting in only 1 to 3 months' extension of overall survival (OS)3–5. Moreover, the presence of a BRCA pathogenic germline variant is identified in only 5–7% of patients, while the occurrence of a KRAS G12C mutation is observed in just 1–3% of cases1,4. Thus, it is of pivotal importance to identify and validate novel causative genes and pathways underlying pancreatic cancer progression and metastases.
The phosphoprotein phosphatases (PPPs), a subset of the protein phosphatase family, play critical roles in various physiological and pathological processes, including mitosis and cancer6. Among the PPPs family, encompassing PP1 to PP7, PP2A has been extensively investigated and recognized as a tumor suppressor for its ability to inhibit oncogenic regulators such as MYC7. However, the roles of other PPP family members in the progression and metastases of cancer have been less explored. In a recent study, we investigated the expression and potential functions of all PPPs catalytic subunit genes in pancreatic cancer8. Analysis of public databases revealed notable differences in mRNA expression levels of PPP1CA, PPP1CB, PPP3CA, PPP3CB, PPP4C and PPEF1 between pancreatic cancer and adjacent normal tissues. Furthermore, significant correlations between PPP1CA, PPP1CB, PPP3CA, PPP3CB, PPP4C, and OS were identified using the TCGA database. Notably, among these, only PPP3CB exhibited associations with both OS and TNM stage in pancreatic cancer.
PPP3, consisting of catalytic (PPP3C) and regulatory (PPP3R) subunits, is expressed in multiple isoforms. PPP3CA, PPP3CB, and PPP3CC are the three isoforms of PPP3C, which is known for its involvement in T-lymphocyte activation and immunosuppression9. A pivotal member of the PPPs group, PPP3CB harbors a catalytic domain, a calcineurin B-binding segment, a calmodulin-binding segment, and an autoinhibitory segment10,11. Accumulated evidence suggests the role of PPP3CB in cancer. For example, in Herceptin-resistant cells, PPP3CB has been implicated in the regulation of p-FOXO3a levels, influencing its transcriptional activity and, consequently, impacting the negative feedback inhibition of IGF2-triggered IGF-1R/Akt/mTOR signaling12. In addition, PPP3CB has been associated with enhanced anticancer efficacy in nasopharyngeal carcinoma13. In pancreatic cancer, Tahira et al. identified statistically significant expression signatures, including PPP3CB, correlated with pancreatic cancer metastasis14. Despite these findings, the function and potential molecular mechanism of PPP3CB in pancreatic cancer remains largely unknown.
ATOH8, a member of the basic helix-loop helix (bHLH) protein family, serves as a transcriptional regulator influencing various cellular processes such as proliferation, metabolism, apoptosis, and autophagy15. Interestingly, the role of ATOH8 in cancer appears to be dual, exerting pro-cancer or anti-cancer effects depending on the specific cancer type. Elevated levels of ATOH8 have been observed in renal cell cancer, prostate cancer, colorectal cancer, and breast cancer, showing correlation with poor prognosis in patients16–19. Conversely, decreased expression of ATOH8 has been associated with a proliferative and mesenchymal subgroup of gliomas, hepatocellular carcinomas, and nasopharyngeal carcinomas20–23. In a study by Wang et al., ATOH8 was found to be correlated with epithelial-mesenchymal transition (EMT) markers like E-cadherin, and its suppression was shown to enhance the process of EMT23.
In this study, we found that PPP3CB is low expressed in PDAC cell and human cancer specimens and negatively correlated with tumor stage of PDAC. Notably, PPP3CB played a pivotal role in modulating the nuclear translocation of ATOH8, which further transcriptionally inhibits Sp1 expression. These findings unveil key mechanisms within the PPP3CB/ATOH8/Sp1 regulatory axis in PDAC, offering valuable insights into potential targets for innovative tumor-targeting therapeutic strategies.