Cancer Letters

Cancer Letters

Volume 458, 28 August 2019, Pages 56-65
Cancer Letters

Mini-review
COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer

https://doi.org/10.1016/j.canlet.2019.05.024Get rights and content

Highlights

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    KMT2C/D methyltransferases are frequently mutated in cancer.

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    KMT2C/D mutations frequently co-occur in lung cancer.

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    Somatic loss of KMT2C/D function as drivers of oncogenesis.

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    KMT2C/D function to maintain epithelial states.

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    MLR COMPASS complexes control gene transcriptional enhancer functions.

Abstract

The KMT2 (lysine methyltransferase) family of histone modifying proteins play essential roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many blood and solid tumor cancers. The KMT2A-D proteins are histone 3 lysine 4 (H3K4) methyltransferases embedded in large COMPASS-like complexes important for RNA Polymerase II-dependent transcription. KMT2 mutations were initially associated with pediatric Mixed Lineage Leukemias (MLL) and found to be the result of rearrangements of the MLL1/KMT2A gene at 11q23. Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer. Recent studies have provided a better understanding of the potential roles of disrupted KMT2C and KMT2D family proteins in cell growth aberrancy. These findings, together with an examination of cancer genomics databases provide new insights into the contribution of KMT2C/D proteins in epigenetic gene regulation and links to carcinogenesis.

Introduction

Post-translational histone modifications provide a vast epigenetic regulatory language that can be written and decoded by a large number of proteins and are important for controlling the timing and level of gene expression among all eucaryotes [1]. The methylation of lysine residues on N-terminal histone tails can provide both gene activation and repression signals and is one of the best-studied epigenetic modifications [2]. Methylation of histone 3 lysine 4 (H3K4) is frequently associated with active transcription, with di- and trimethylated H3K4 associated with active gene promoters and monomethylation found at gene enhancers [3]. The enzymes that place methyl modifications or marks on H3K4 are known as the KMT2 (lysine methyltransferase) family and are found embedded within enormous protein complexes, named COMPASS (COMplex of Proteins ASsociated with SET1) [4]. The discovery almost 30 years ago of recurrent translocation-associated leukemias involving MLL1/KMT2A, a homolog of the Drosophila Trithorax (Trx) protein important in Hox gene regulation, provided a critical platform for investigations into the roles of the KMT2 proteins in animal development and cancer [[5], [6], [7]]. More recently, genes encoding other KMT2 family proteins have been implicated in cancer [8]. Tumor genome and exome sequencing studies combined with cancer cell and model system genetic analyses over the past decade have revealed an unanticipated vital role for the KMT2 family enzymes in a diverse set of cancers, both as drivers of oncogenesis and as critical cooperating mutations in both cancer progression and post-therapy relapse.

Section snippets

KMT2 COMPASS-like complexes

KMT2 family proteins (SET1A, SET1B, MLL1/KMT2A, MLL4(2)/KMT2B, MLL3/KMT2C and MLL2(4)/KMT2D) provide the histone lysine methyltransferase activity of mammalian COMPASS complexes. Designated MLL1-5 based on relatedness to the MLL1 gene (Mixed Lineage Leukemia), KMT2 proteins comprise three subgroups, called COMPASS and COMPASS-like based homology with Drosophila Trx, Trr and dSet1 [4,8]. Genome duplication during mammalian evolution resulted in two paralogs in each KMT2 subgroup. KMT2A/MLL1 and

Emerging roles for KMT2C and KMT2D in cancer

The epigenetic functions of the COMPASS complexes are vital for normal animal development and frequent mutations affecting these proteins or other components of the COMPASS complexes are associated with a large number of cancers [32]. Mutations involving KMT2 family genes are among the most commonly seen in many diverse cancer types and there is a statistically significant co-occurrence, raising the possibility that the simultaneous disabling of several KMT2 genes might be a critical step in

Lessons from KMT2C/D mutations in lung cancer

Lung cancers, both non small cell (NSCLC, 85%) and small cell (SCLC, 15%), are a leading cause of cancer-associated deaths worldwide with few treatment options and a high recurrence rate. SCLC is a highly aggressive neuroendocrine tumor with a very poor prognosis in which TP53 and RB1 are frequently mutated. Several whole genome or exome sequencing studies have also revealed a high frequency of KMT2D (8–24%) but not KMT2C mutations [[55], [56], [57], [58], [59], [60], [61]]. These studies

Functional distinctions between KMT2C and KMT2D in cancer

Possible oncogenic mechanisms associated with KMT2C/D loss involve the dysregulation of transcriptional enhancers and transcription factor-dependent programs that drive cellular pathways required for tumor suppression and anti-tumor immune evasion [12,21]. For example, several studies have demonstrated important direct interactions between KMT2C/D and the tumor suppressor TP53 [[74], [75], [76], [77], [78]]. The activation of TP53 target genes following doxorubicin (DNA damaging agent)

Germline roles of KMT2-family genes in cancer predisposition

The KMT2A-D genes are each essential for organismal viability, with strong depletion, homozygous loss of function mutations or deletions resulting in embryonic or perinatal lethality (KMT2A/MLL1: [86,87]; KMT2B/MLL4(2): [88]; KMT2C/MLL3 and KMT2D/MLL2(4): [81,89]. Somatic mutations in the KMT2A-D genes have been strongly linked to cancer development; however, it is less clear the impacts of de novo germline mutations in cancer predisposition. The KMT2A-D genes have each been associated with

Conclusions and perspectives

Cancer exome databases reveal that the KMT2C/MLL3 and KMT2D/MLL2(4) histone lysine methyltransferases are among the most frequently mutated genes across a variety of cancer types. Most of these cancers are associated with mutations that alter the proteins through missense changes or truncations resulting in reduced functions, supporting their roles as tumor suppressors. Genetic removal of these genes in cancer cells, embryonic stem cells, as well as both vertebrate and invertebrate animal

Author contributions

AD and RF conceived the idea for the review, researched the literature and wrote the manuscript.

Conflict of interest statement

The authors declare that they have no competing financial interests.

Acknowledgements

We thank Claudia Zraly, David Ford and Matthew Kroll for helpful advice and comments on the manuscript. R. F. was supported by a NIH T35 award from the NHLBI (HL120835). The research in the laboratory of A.D. is supported by the National Science Foundation (MCB1716431).

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