INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma

Abstract

Superenhancers (SEs) are large genomic regions with a high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, a chromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi. Furthermore, Ino80 silencing selectively inhibits melanoma cell proliferation, anchorage-independent growth, tumorigenesis, and tumor maintenance in mouse xenografts. Mechanistically, Ino80 occupies >90% of SEs, and its occupancy is dependent on transcription factors such as MITF and Sox9. Ino80 binding reduces nucleosome occupancy and facilitates Mediator recruitment, thus promoting oncogenic transcription. Consistently, genes co-occupied by Ino80 and Med1 are selectively expressed in melanomas compared with melanocytes. Together, our results reveal an essential role of INO80-dependent chromatin remodeling in SE function and suggest a novel strategy for disrupting SEs in cancer treatment.

Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers

“…Based on the frequent deep deletions noted in PDAC TCGA datasets, we additionally examined the effects of INO80C deletion in a KRAS MUT PDAC cell line, Capan-2, and found that it also enhanced tumor growth in vivo. While the SWI/SNF family of chromatin remodelers, which are frequently mutated or lost in many tumors including PDAC, have been more widely studied, the INO80 complex has recently been implicated in carcinogenesis (39,40). INO80 is a large multi-subunit complex that maintains genome stability through nucleosome editing, such as removal of the histone variant H2A.Z (41).…”

Super-Enhancer-Driven Transcriptional Dependencies in Cancer

“…These observations suggested that, similar to normal cells, cancer-associated SE domains mark lineage-restricted genes as well as putative oncogenes that normally serve as critical regulators of cell proliferation and apoptosis. Indeed, SEs mark lineage-specific TFs and oncogenes in a broad spectrum of cancers, including neuroblastoma [20], small-cell lung cancer (SCLC) [21], medulloblastoma [40], breast [41], esophageal [42] and gastric [43] cancers and melanoma [44]. The SEs associated with key oncogenes are unique to cancer cells and conspicuously absent in normal untransformed cells of identical lineage, suggesting that they are acquired during the course of tumorigenesis and underlie the oncogenic state in fundamental ways [17].…”

H2B monoubiquitination: t'ub or not t'ub for inducible enhancers

“…Because the dissociation of H2B-H2A or H2B-H2A variant dimers is the first step in nucleosome disassembly, 1 the stabilization of H2B-H2A.Z dimers by H2Bub1 impairs DNA accessibility upon enhancer induction and is responsible for the repression of inducible transcription. We provided a mechanism by showing that the monoubiquitination of H2B blocks the eviction of H2A.Z by impairing the interaction of the chromatin remodeller INO80 15 with H2B.…”