Histone demethylase KDM3A is required for enhancer activation of hippo target genes in colorectal cancer

Abstract

Hippo pathway is involved in tumorigenesis, and its regulation in cytosol has been extensively studied, but its regulatory mechanisms in the nuclear are not clear. In the current study, using a FBS-inducing model following serum starvation, we identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. KDM3A promotes gene expression through two mechanisms, one is to upregulate YAP1 expression, and the other is to facilitate H3K27ac on the enhancers of hippo target genes. H3K27ac upregulation is more relevant with gene activation, but not H3K4me3; and KDM3A depletion caused H3K9me2 upregulation mainly on TEAD1-binding enhancers rather than gene bodies, further resulting in H3K27ac decrease, less TEAD1 binding on enhancers and impaired transcription. Moreover, KDM3A is associated with p300 and required for p300 recruitment to enhancers. KDM3A deficiency delayed cancer cell growth and migration, which was rescued by YAP1 expression. KDM3A expression is correlated with YAP1 and hippo target genes in colorectal cancer patient tissues, and may serve as a potential prognosis mark. Taken together, our study reveals novel mechanisms for hippo signaling and enhancer activation, which is critical for tumorigenesis of colorectal cancer.

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

“…As prior work veri ed, M2 macrophage can be induced by KDM3A [21]. Additionally, it is addressed that KDM3A, a demethylase of histone H3K9me1/2, can promote the expression of CTGF by facilitating H3K27ac on the enhancers of CTGF [22]. While CTGF promotes drug-resistance in glioblastoma cells and facilitates the progression of glioblastoma [23].…”

Histone demethylase Jumonji domain‐containing 1A inhibits proliferation and progression of gastric cancer by upregulating runt‐related transcription factor 3

“…Increasing evidence has shown that JMJD1A promotes proliferation, survival, and metastasis in several types of cancers, including prostate cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, bladder cancer, and Ewing sarcoma 14‐20,31‐34 . Moreover, it has been reported that JMJD1A is downregulated in nasopharyngeal carcinoma (NPC) and downregulation of JMJD1A is associated with poor prognosis of NPC patients 35 .…”

“…JMJD1A plays crucial roles in various cellular processes, including spermatogenesis, 7 energy metabolism, 8,9 sex determination, 10 stem cell self‐renewal, 11,12 and differentiation 13 . JMJD1A is shown to play a tumor‐promoting role in several types of cancers, such as colorectal cancer, prostate cancer, hepatocellular carcinoma, ovarian cancer, and bladder cancer 14‐20 . Although JMJD1A has been shown to be a predictor for prognosis and a potential therapeutic target for GC, 21 the role and the underlying mechanism of JMJD1A in GC progression remain to be further elucidated.…”

Loss of heterochromatin and retrotransposon silencing constitute an early phase in oocyte aging

“…5C, S9). Since heterochromatin that is characterized by H3K9me2 and binding of HP1γ is also associated with a histone de-acetylation on H3K27 (Naruse et al, 2020) (Wang et al, 2019), we sought to investigate whether inhibiting the deacetylation of histones in oocytes will cause a similar effect. Previous reports also showed that treatment with a histone deacetylase (HDAC) inhibitor affects oocyte maturation in-vitro (Jin et al, 2014).…”