Abstract C083: Kaiso defines distinct chromatin and protein interaction networks in breast cancer: Implications for precision therapy

Abstract The fact that breast cancer exhibits notable individual and racial variations in incidence, prognosis, and response to treatment. This highlights the need for a more thorough examination of the molecular mechanisms underlying these differences. KAISO (ZBTB33), long recognized as a methyl-CpG binding protein and transcriptional repressor, is increasingly understood to have more complex regulatory roles. KAISO has two DNA-binding sites: a methylated CpG motif and a consensus sequence unique to KAISO. Previous ATAC-seq study showed that KAISO can localize to the areas of open chromatin in different cancer cells, indicating possible roles beyond repression. Based on this data, we hypothesized that KAISO might interact with important regulatory proteins and form unique chromatin complexes to contribute to both transcriptional repression and activation. To investigate this, we analyzed MCF7 (luminal, Non-Metastatic, European American origin) and HCC1806 (Basal, Metastatic, African American origin) breast cancer cell lines, which differ in molecular subtype and racial background. We used Cut&Run to construct genome-wide KAISO binding profiles and Rapid Immunoprecipitation Mass Spectrometry of Endogenous Protein (RIME) to map KAISO-interacting protein networks. Our RIME data showed clear distinctions between the two lines: in HCC1806, KAISO strongly associated with molecular chaperones (HSPA8, HSP90AB1), elongation factor (EEF1A1), and immune-related proteins (e.g., C4B, APOC3), while MCF7 interactions favored structural and co-regulatory proteins (e.g., MYH10, CLTC, RBMXL1). Different chromatin engagement patterns were revealed by Cut&Run profiling. With promoter-associated peaks at about 90 locations, MCF7 showed an abundance of intronic (∼160 peaks) and intergenic binding (∼110 peaks), encompassing genes such as ATP9B, LINC01667, and TSPAN9. HCC1806, on the other hand, showed greater intronic enrichment (∼140 peaks) and fewer promoter peaks (∼50). All of these results point to KAISO's potential as a molecular marker for precision oncology by indicating that it is involved in transcriptional regulatory complexes that are unique by subtypes (Basal/Luminal, Metastatic/Non-Metastatic) in breast cancer. In order to further understand the regulatory function of KAISO, ongoing research attempts to expand these investigations to more related cell lines. Citation Format: Sazaul Morshed Sazib, Huixian Lin, Aliyu Muhammad, Md. Abu Siddique, Isra Elhussin, Moray Campbell, Shahjalal Chowdhury, Samuel Mwamburi, Malik McRae, Balasubramanyam Karanam, Clayton Yates. Kaiso defines distinct chromatin and protein interaction networks in breast cancer: Implications for precision therapy [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C083.