Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A–PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1

•We show that the PAH2 domain of SIN3A is a target when it is inhibited from binding to PF1 results in inhibition of invasive phenotype in TNBC.•Epigenetic repression of integrins expression and downstream pathways results from enhanced binding of KLF9 /SIN3A repressor complex to their promoters.•Genome wide transcriptomic analysis showed downregulation of multiple invasion related genes. Tumor growth and lung metastasis were markedly decreased in vivo.•Our studies highlight that PF1 might serve as a gatekeeper for trafficking SID protein binding to PAH2 of SIN3A and has functional role in presentation of different regulatory complexes.•Blocking the function of PAH2 offers a promising targeted therapy approach for inhibiting the invasive phenotype in TNBC. SIN3A, a scaffold protein has regulatory functions in tumor biology. Through its Paired amphipathic helix (PAH2) domain, SIN3A interacts with PHF12 (PF1), a protein with SIN3 interaction domain (SID) that forms a complex with MRG15 and KDM5A/B. These components are often overexpressed in cancer. In the present study, we evaluated the role of SIN3A and its interacting partner PF1 in mediating inhibition of tumor growth and invasion in triple negative breast cancer (TNBC). We found profound inhibition of invasion, migration, and induction of cellular senescence by specific disruption of the PF1/SIN3A PAH2 domain interaction in TNBC cells expressing PF1-SID transcript or peptide treatment. Genome-wide transcriptomic analysis by RNA-seq revealed that PF1-SID downregulates several gene sets and pathways linked to invasion and migration. Integrin α6 (ITGA6) and integrin ß1 (ITGB1) and their downstream target proteins were downregulated in PF1-SID cells. We further determined increased presence of SIN3A and transcriptional repressor, KLF9, on promoters of ITGA6 and ITGB1 in PF1-SID cells. Knockdown of KLF9 leads to re-expression of ITGA6 and ITGB1 and restoration of the invasive phenotype, functionally linking KLF9 to this process. Overall, these data demonstrate that specific disruption of PF1/SIN3A, inhibits tumor growth, migration, and invasion. Also, PF1-SID not only inhibits tumor growth by senescence induction and reduced proliferation, but it also targets cancer stem cell gene expression and blocks mammosphere formation. Overall, these data demonstrate a mechanism whereby invasion and metastasis of TNBC can be suppressed by inhibiting SIN3A-PF1 interaction and enhancing KLF9 mediated suppression of ITGA6