Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma

Maitituoheti, Mayinuer; Keung, Emily Z.; Tang, Ming; Liang, Yan; Alam, Hunain; Han, Guangchun; Raman, Ayush T.; Terranova, Christopher; Sarkar, Sharmistha; Orouji, Elias; Amin, Samir B.; Sharma, Sneha; Williams, Maura; Samant, Neha S.; Dhamdhere, Mayura; Zheng, Norman; Shah, Tara; Shah, Amiksha; Axelrad, Jacob B.; Anvar, Nazanin Esmaeili; Lin, Yu-Hsi; Jiang, Shan; Chang, Edward; Wang, Wei‐Lien; Ingram, Davis R.; Lazar, Alexander J.; Lee, Min Gyu; Müller, Florian; Wang, Linghua; Ying, Haoqiang; Rai, Kunal

doi:10.2139/ssrn.3551616

Cited by 10 publications

(22 citation statements)

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“…Our data also demonstrates enhancer reprogramming in KMT2D-deficient head and neck cancers. This is consistent with our previous studies where similar reprogramming of H3K4me1marked enhancer states were observed in KMT2D-deficient cells (Maitituoheti et al, 2020).…”

Section: Discussionsupporting

confidence: 94%

“…All cell lines were cultured at 37 °C in an atmosphere of 5% CO2. Human KMT2D knockdown experiments were performed in the HN30 cell line using KMT2D-specific shRNAs described previously (Maitituoheti et al, 2020). Knockdown experiments for the mouse MOC1 cell line were done using the SMARTvector Inducible Lentiviral shRNA system from Horizon Discovery: V3SM11253-233092640 (sh-KMT2D) and VSC11658 (sh-nontargeting).…”

Section: Cell Culturementioning

confidence: 99%

“…KMT2D is a histone lysine methyltransferase with a variety of critical functions, ranging from regulation of metabolism in cancer to control of skin homeostasis in conjunction with p63 (Koutsioumpa et al, 2019;Lin-Shiao et al, 2018;Maitituoheti et al, 2020). To study the effects of KMT2D loss in HNSCC, we first generated KMT2D knockdown (KD) in the established HNSCC cell line HN30 and performed RNA-seq.…”

Section: Kmt2d Regulates Response To Interferon and Cytokine Signalingmentioning

confidence: 99%

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KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment

Callahan

Divenko

Barrodia

et al. 2021

Preprint

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with 5-year survival of approximately 50%. Genomic profiling studies have identified important somatic mutations in this disease which presents an opportunity for precision medicine. We demonstrate that KMT2D, a histone methyltransferase harbors somatic mutations in approximately 17% of HNSCC and is associated with 2-year recurrence in TCGA data. Consistent with algorithmic prediction of bring a driver tumor-suppressor event, its loss results in larger oral tumors in immune-proficient orthotopic models. Mechanistically, we find that KMT2D knockdown or KMT2D mutation causes loss of H3K4me1-marked enhancers harboring IRF7/9 binding sites, which is known to regulate interferon signaling. Indeed, KMT2D loss in human and murine cell lines deregulated transcriptional levels of cytokine expression and impacted numerous immune signaling pathways, including interferon signaling. Consistently, Kmt2d knockdown in murine tumors exhibited decrease in IFN gamma-producing effector T cells and an increase in T-cells with an exhausted phenotype. Epistasis experiments showed that exogenous treatment with IFN gamma abrogated the increased tumor growth in Kmt2d-deficient oral tumors. Together, these results support the role of KMT2D as a tumor suppressor in HNSCC that regulates the tumor microenvironment by modulating H3K4me1-marked enhancers controlling interferon signaling.

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Section: Discussionsupporting

confidence: 94%

Section: Cell Culturementioning

confidence: 99%

Section: Kmt2d Regulates Response To Interferon and Cytokine Signalingmentioning

confidence: 99%

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KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment

Callahan

Divenko

Barrodia

et al. 2021

Preprint

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“…Our data also show selective sensitivity in mitochondrial oxidative phosphorylation deficient cancers driven by TCA cycle loss-of-function mutations as well as those “addicted” to glycolysis due to mutations in VHL 11 , 12 , 59 ( Extended Data Figure 7 ). Beyond these defined genomic populations with Enolase deficiencies, unique sensitivity to Enolase inhibition has also been documented in other genetic settings 60 , 61 testifying to greater utility of POMHEX and HEX. Thus, for the first time, we have provided in vivo proof-of-principle for the decisive efficacy of collateral lethality through pharmacological inhibition of Enolase.…”

Section: Discussionmentioning

confidence: 99%

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

et al. 2020

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Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We previously identified a subset of cancers harboring homozygous deletion of the glycolytic enzyme Enolase (ENO1) with exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small molecule Enolase inhibitor, POMHEX, can selectively kill ENO1 -deleted glioma cells at low nanomolar concentrations and eradicate intracranial orthotopic ENO1 -deleted tumors in mice at doses well-tolerated in non-human primates. Our data provide in vivo proof-of-principal for the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential across a range of therapeutic settings.

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“…For example, copy number alterations encompassing an IGFBP5 enhancer on 2q35 modulate breast cancer risk (40). In melanoma, a recent preprint reported that inactivation of IGFBP5 distal enhancers down-regulates IGFBP5 expression and promotes melanomagenesis by inducing an IGF1R-AKT signalling-dependent increase in glycolysis and metabolic reprogramming (41). Consistent with this, IGFBP5 negatively regulates IGFR1 and MAPK kinase signalling to inhibit melanoma proliferation and metastasis, whilst IGFBP5 overexpression reduces the anchorage-independent growth of A375 melanoma cells (36).…”

Section: Discussionmentioning

confidence: 99%

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Coe

Tan

Shapiro

et al. 2019

Preprint

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The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identified 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. We characterise the function and molecular mechanism of action of one of these lncRNAs, Disrupted In Renal Carcinoma 3 (DIRC3), and show that it operates as a MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that functions locally to activate expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in multiple cancer associated processes. Our work indicates that lncRNA components of the MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets.

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Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma

Cited by 10 publications

References 0 publications

KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment

KMT2D Loss Promotes Head and Neck Squamous Carcinoma Through Enhancer Reprogramming and Modulation of Immune Microenvironment

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

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