Transcriptional Addiction in Cancer

Abstract

Cancer arises from genetic alterations that invariably lead to dysregulated transcriptional programs. These dysregulated programs can cause cancer cells to become highly dependent on certain regulators of gene expression. Here, we discuss how transcriptional control is disrupted by genetic alterations in cancer cells, why transcriptional dependencies can develop as a consequence of dysregulated programs, and how these dependencies provide opportunities for novel therapeutic interventions in cancer.

Figure 1. Genetic changes and dysregulated gene expression programs lead to cancer cell state

The path to a cancer cell involves genetic alterations that lead to changes in the gene expression program. The dysregulated program can create dependencies on transcriptional regulators that make the tumor cells more sensitive to inhibition of these regulators than normal cells.

Figure 2. Key features of transcriptional regulation of gene expression programs

A) In this model of cell-type specific core regulatory circuitry, master TFs co-regulate their own genes, forming an interconnected autoregulatory loop (left), as well as those of those of many other cell-type specific genes (right). B) Enhancers are DNA elements bound by multiple TFs that recruit coactivators (such as Mediator) and RNA polymerase II, which can initiate transcription within enhancer sequences to produce enhancer RNAs (eRNAs). C) SE constituents are physically connected. Interactions among SE constituent enhancers, and between SEs and a target gene are indicated by red arcs. D) Human genome contains over 10,000 insulated neighborhoods, which are produced by multimerization of CTCF bound to two sites and reinforced with cohesin; enhancer-gene interactions occur predominantly within these neighborhoods. E) SEs are enriched for signaling transcription factors, and their associated genes, which tend to play prominent roles in cell identity, are thus especially responsive to signaling. F) Signaling TFs and other TFs that play important regulatory roles are themselves regulated by ubiquitin and proteasome-mediated destruction. G) Chromatin regulators that act through “writing”, “erasing” or “reading” histone modifications. H) DNA methylation can contribute to gene control by causing loss of TF binding at enhancers and loss of CTCF at insulated neighborhood loop anchors.

Figure 3. Components of gene control altered in cancer

Examples of three types of cis-factors (enhancers, promoters and insulators) and various trans-factors (transcription factors, cofactors, chromatin regulators, RNA polymerase II and histones) that acquire recurrent somatic mutations in cancer cells.

Figure 4. Common mechanisms of dysregulation of gene expression programs in cancer involving trans-factors

A) Model of a transcriptional regulatory circuit controlling the gene expression program in normal cells is shown top left. Dysregulation of gene expression programs in cancer cells can occur through dysregulation an oncogenic master TFs (bottom left), dysregulation of a transcriptional amplifier (e.g. MYC) (bottom right), and dysregulated signaling (top right). B) Model of aberrant chromatin modification affecting gene expression programs in cancer cells. C) Model of effect of cohesin mutations and CTCF mutations on enhancer-promoter interactions and insulated neighborhoods in cancer cells.

Figure 5. Common mechanisms of dysregulation of gene expression programs in cancer involving cis-factors

A) Mechanisms leading to the acquisition of super-enhancers to drive oncogenes in cancer cells: translocation of an existing super-enhancer, focal amplification of an enhancer element, and nucleation of super-enhancer through somatic insertion of transcription factor binding sites. B) Activation of silent proto-oncogenes by somatic mutations that disrupt insulated neighborhood anchor sites.

Figure 6. Drugging transcriptional dependencies

A) Model of the features of super-enhancer –associated oncogene control that contribute to transcriptional dependencies. B) Model of the mechanistic basis of higher transcriptional activity and vulnerability of super-enhancers: co-operative interactions between the co-activators recruited to these sites. C) Therapeutic strategy to inhibit transcriptional dependencies due to aberrant recruitment of DOT1L to driver genes in MLL-AF fusion leukemias. D) Therapeutic strategy to attack small populations of drug-tolerant tumor cells with histone deacetylase inhibitors. E) Therapeutic strategy to downregulate oncogenes through manipulation and repair of insulated neighborhoods. F) Targeted degradation of transcriptional regulators using degronimids that recruit E3-ubiquitin ligase for proteasome-mediated degradation.