Abstract
Epigenetic mechanisms are central to understanding the molecular basis underlying tumorigenesis. Aberrations in epigenetic modifiers alter epigenomic landscapes and play a critical role in tumorigenesis. Notably, the histone lysine methyltransferase KMT2D (a COMPASS/ Set1 family member; also known as MLL4, ALR, and MLL2) is among the most frequently mutated genes in many different types of cancer. Recent studies have demonstrated how KMT2D loss induces abnormal epigenomic reprograming and rewires molecular pathways during tumorigenesis. These findings also have clinical and therapeutic implications for cancer treatment. In this review, we summarize recent advances in understanding the role of KMT2D in regulating tumorigenesis and discuss therapeutic opportunities for the treatment of KMT2D-deficient tumors.
Highlights
Covalent modifications of histones sophisticatedly regulate chromatin architecture [1,2,3,4]
We have shown that brain-specific loss of Kmt2d alone induces spontaneous medulloblastoma in 34.6% of brains in a genetically engineered mouse model (GEMM) [31]
In a breast cancer study, we showed that KMT2D knockdown inhibited cell proliferation and invasion of triple–negative breast cancer cell lines and that KMT2D and KMT2D-interacting histone demethylase UTX co-activated gene expression programs for cell proliferation and invasion [44]
Summary
Covalent modifications of histones sophisticatedly regulate chromatin architecture [1,2,3,4]. Maitituoheti et al [33] showed that Kmt2d loss promoted melanoma in a GEMM and that KMT2D downregulated www.oncotarget.com expression of glycolytic genes by increasing expression of IGFBP5, a tumor suppressor and negative regulator of IGF1R signaling. A study using estrogen receptor (ER)-positive breast cancer cell lines showed that KMT2D knockdown reduced cell viability and increased the sensitivity of xenograft tumors to a PI3Kα inhibitor.
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