Mechanistic Understanding Of Regulators Involved In Malignancy Of Tumor Cells

Abstract

quotCancer remains a leading cause of mortality worldwide, responsible for approximately 9.7 million newlinedeaths in 2022 according to the World Health Organization (WHO). Krüppel-like factors (KLFs), newlinea family of zinc-finger transcription factors, regulate pivotal cellular processes including newlineproliferation, differentiation, migration, and apoptosis. Dysregulation of KLF activity, frequently newlinemediated by post-translational modifications (PTMs), is implicated in tumorigenesis and tumor newlineprogression. PTMs modulate the biological function of proteins via alterations in activation state, newlinesubcellular localization, stability, solubility, folding, substrate interactions, and protein-protein newlineinteractions. Amino acid residues targeted by PTMs act as molecular switches, influencing protein newlinefunction and amplifying proteome complexity. These modifications impact diverse cancer relevant pathways. Elucidating post-translational modifications (PTMs) of these transcription newlinefactors can unveil insights into protein function, activity, subcellular localization, solubility, newlinefolding, substrate binding, and protein-protein interactions. newlineWe initiated our work by investigating Post-Translational Modifications (PTMs) of KLF Group 2 newlinetranscription factors involved in cancer progression. This study examines the complex interplay newlinebetween cancer, metastasis, and the regulatory role of post-translational modifications (PTMs) on newlineKLF group 2 transcription factors. We investigated the differential impact of acetylation and newlinephosphorylation on the interactions of KLF group 2 members with their binding partners. Notably, newlinethese modifications have variable effects depending on the specific KLF protein and the modified newlineresidue. Our findings indicate that KLF2-EP300, KLF4-EP300, KLF4-SP1, KLF5-CBP, KLF5- newlineWWP1, KLF6-ATF3, KLF6-JUN, and KLF7-JUN are stabilized following acetylation or newlinephosphorylation. Conversely, KLF4-EP300, KLF5-WWP1, KLF6-SP1, and KLF7-ATF3 exhibit newlinedestabilization due to these PTMs. These results elucidate the molecular mechanis