Hydrogen sulfide and carbon monoxide as possible regulators of YY1 and RKIP: Novel insights into gastrointestinal cancers pathogenesis

Gastrointestinal (GI) cancers remain among the leading causes of cancer-related mortality, with challenges in early detection, therapeutic resistance, and poor prognosis. Two key molecular players, Yin Yang 1 (YY1) and Raf kinase inhibitor protein (RKIP), have emerged as important regulators of cancer progression and treatment response. This review highlights their individual and interactive roles across various GI malignancies, including gastric, colorectal, pancreatic, and liver cancers. Evidence indicates an antagonistic relationship, where YY1 promotes tumor growth and epithelial-mesenchymal transition (EMT), while RKIP counters these effects by suppressing oncogenic signaling pathways. On the other hand, endogenous gaseous transmitter, nitric oxide (NO) has been clearly shown to influence the YY1-RKIP axis. NO directly inhibits YY1 via S-nitrosylation and promotes RKIP expression, reinforcing pro-apoptotic and anti-metastatic pathways. Although some scientific evidence exists, the role of another gaseous mediator, hydrogen sulfide (H₂S), as a modulator of YY1 or RKIP remains poorly characterized. Its regulatory influence, especially via interaction with NO signaling, suggests a complex, context-dependent role. H₂S/sulfides-mediated posttranslational modification of proteins – persulfidation - has been shown recently to be functionally important but not in the context of YY1 or RKIP activity. Moreover, carbon monoxide (CO) that interacts with metalloproteins has been completely overlooked as possible regulator of YY1/RKIP-dependent cancer biology. Therefore, we indicate here the possible interplay between H₂S and CO with YY1/RKIP that may provide new further scientific direction in this field, based on aggressive GI tumors.