Sin3b, a paired amphipathic helix protein, serves as a scaffold for chromatin-modifying complexes. It represses gene transcription, regulating distinct biological processes such as cell cycle withdrawal, which is crucial for preventing tumor progression [1]. Sin3b-containing complexes, through association with the Rb family of proteins, repress E2F target gene expression during quiescence, differentiation, and senescence [1]. Genetic models like zebrafish and mice are valuable for studying its functions.

In murine PDAC models, tumor-cell intrinsic Sin3b loss reshapes the tumor microenvironment, increasing CD8+ T-cell infiltration and cytotoxicity, and enhancing sensitivity to anti-PD1 treatment [2]. In hepatocellular carcinoma, Sin3b promotes integrin αV subunit gene transcription and cell migration, with its function influenced by sulfatide [3]. In cancer cells, Sin3b inactivation delays DNA double-strand break resolution and sensitizes cells to DNA-damaging agents, while also affecting DNA repair pathway choice [4]. In humans, SIN3B haploinsufficiency causes a syndromic intellectual disability/autism spectrum disorder [5]. In zebrafish, sin3b mutants have size, skeletal, and locomotor defects [6]. In a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression by inducing senescence [7]. Fibroblasts genetically inactivated for Sin3B are refractory to replicative and oncogene-induced senescence [8].

In conclusion, Sin3b is essential for regulating gene transcription, cell cycle, and DNA damage repair, playing a role in cancer, neurodevelopmental disorders, and other biological processes. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have significantly contributed to understanding Sin3b's functions in these disease areas, highlighting its potential as a therapeutic target.