JARID1B Is a Luminal Lineage-Driving Oncogene in Breast Cancer

Abstract

SUMMARY Recurrent mutations in histone modifying enzymes imply key roles in tumorigenesis yet their functional relevance is largely unknown. Here we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor positive breast tumors.

A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine

“…Recent studies (4,6) have highlighted the importance of KDM5B in breast cancer oncogenesis. Accordingly, we screened 36 breast cancer cell lines for sensitivity to CPI-455 (Supp.…”

“…Whereas FAD-dependent KDM’s can only remove H3K4me1 and H3K4me2, the four homologous KDM5 proteins (KDM5A-D) also catalyze the removal of H3K4me3 (3–5). Importantly, KDM5A and KDM5B are overexpressed or amplified in a number of human cancers and have been described as critical regulators of tumorigenesis (4,6), making these proteins ideal candidates for targeted inhibition with small molecules.…”

Portrait of the PI3K/AKT pathway in colorectal cancer

“…However, it is likely that changes in the promoter or other regulatory sequences will be found to have functional consequences as more studies are investigating this genomic dark matter [70,71]. Increasingly evident is the importance of alterations of epigenetic regulators in cancer development and on clinical strategies [72]. In contrast, hot-spot mutations in the genes constituting the canonical PI3K/AKT pathway are well studied in all the major cancer types and a vast number of papers containing mutational data for colorectal cancer specimens have been and are continuously being published, emphasizing the interest in this particular signaling network.…”

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

“…Moreover, the knockdown of KDM5B by siRNA diminished the cancer cell growth, which purportedly resulted from the decreased expression of E2F1 and E2F2 that are the downstream modulators regulated by KDM5B in the retinoblastoma protein (pRb) pathway (Barrett et al, 2002;Xiang et al, 2007;Yamane et al, 2007;Hayami et al, 2010;Yamamoto et al, 2014). A large number of point mutations have been identified within the KDM5C gene in patients with X-linked mental retardation (XLMR) (Wu et al, 1994;Brown et al, 1995;Jensen et al, 2005;Santos et al, 2006;Tzschach et al, 2006).…”