Full Text Journal Articles by
Author Kunal Rai

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

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

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific ... Read more >>

Cell Rep (Cell reports)
[2020, 33(3):108293]

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Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells.

Teresa Manzo, Boone M Prentice, Kristin G Anderson, Ayush Raman, Aislyn Schalck, Gabriela S Codreanu, Carina B Nava Lauson, Silvia Tiberti, Andrea Raimondi, Marissa A Jones, Michelle Reyzer, Breanna M Bates, Jeffrey M Spraggins, Nathan H Patterson, John A McLean, Kunal Rai, Carlo Tacchetti, Sara Tucci, Jennifer A Wargo, Simona Rodighiero, Karen Clise-Dwyer, Stacy D Sherrod, Michael Kim, Nicholas E Navin, Richard M Caprioli, Philip D Greenberg, Giulio Draetta, Luigi Nezi,

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated ... Read more >>

J. Exp. Med. (The Journal of experimental medicine)
[2020, 217(8):]

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Telomere dysfunction activates YAP1 to drive tissue inflammation.

Deepavali Chakravarti, Baoli Hu, Xizeng Mao, Asif Rashid, Jiexi Li, Jun Li, Wen-Ting Liao, Elizabeth M Whitley, Prasenjit Dey, Pingping Hou, Kyle A LaBella, Andrew Chang, Guocan Wang, Denise J Spring, Pingna Deng, Di Zhao, Xin Liang, Zhengdao Lan, Yiyun Lin, Sharmistha Sarkar, Christopher Terranova, Yonathan Lissanu Deribe, Sarah E Blutt, Pablo Okhuysen, Jianhua Zhang, Eduardo Vilar, Ole Haagen Nielsen, Andrew Dupont, Mamoun Younes, Kalyani R Patel, Noah F Shroyer, Kunal Rai, Mary K Estes, Y Alan Wang, Alison A Bertuch, Ronald A DePinho,

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):4766]

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Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

Elias Orouji, Ayush Raman, Anand Singh, Alexey Sorokin, Emre Arslan, Archit Ghosh, Jonathan Schulz, Christopher Terranova, Ming Tang, Mayinuer Maitituoheti, Carson Callahan, Katarzyna Tomczak, Zhiqin Jiang, Jennifer Davis, Sukhen Ghosh, Hey Min Lee, Laura Reyes-Uribe, Kyle Chang, Yushua Liu, Huiqin Chen, Ali Azhdarnia, Jeffrey Morris, Eduardo Vilar, Kendra Carmon, Scott Kopetz, Kunal Rai,

ABSTRACT The extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could ... Read more >>

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Single-cell Characterization of Acute Myeloid Leukemia and its Microenvironment Following PD-1 Blockade Based Therapy

Hussein Abbas, Dapeng Hao, Katarzyna Tomczak, Praveen Barrodia, Jin Seon Im, Patrick Reville, Zoe Alaniz, Wei Wang, Ruiping Wang, Feng Wang, Gheath Al-Atrash, Koichi Takahashi, Jing Ning, Maomao Ding, Jairo Mathews, Latasha Little, Jianhua Zhang, Sreyashi Basu, Marina Konopleva, Guillermo Garcia-Manero, Michael Green, Padmanee Sharma, James Allison, Steven Kornblau, Kunal Rai, Linghua Wang, Naval Daver, Andrew Futreal,

Abstract Acute myeloid leukemia (AML) and effector cells of immune checkpoint blockade (ICB) therapy co-reside in a complex bone marrow (BM) milieu. The interplay of tumor intrinsic and microenvironment (TME) mechanisms that influences the response to ICB-based therapies in AML have not been elucidated. Here we report our analyses of ... Read more >>

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Immune landscape of a genetically-engineered murine model of glioma relative to human glioma by single-cell sequencing

Daniel Zamler, Takashi Shingu, Laura Kahn, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Cassian Yee, Kunal Rai, Stephanie Watowich, Amy Heimberger, Giulio Draetta, Jian Hu,

SUMMARY Background This study focuses on the evaluation of intratumoral immune infiltrates of the Qk/trp53/Pten (QPP) triple-knockout mouse model of glioblastoma with the purpose of establishing its relevance compared to the human disease. This included an analysis at the single cell level, of immune cells composition in both spontaneous and ... Read more >>

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KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer.

Hunain Alam, Ming Tang, Mayinuer Maitituoheti, Shilpa S Dhar, Manish Kumar, Chae Young Han, Chandrashekar R Ambati, Samir B Amin, Bingnan Gu, Tsai-Yu Chen, Yu-Hsi Lin, Jichao Chen, Florian L Muller, Nagireddy Putluri, Elsa R Flores, Francesco J DeMayo, Laura Baseler, Kunal Rai, Min Gyu Lee,

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and ... Read more >>

Cancer Cell (Cancer cell)
[2020, 37(4):599-617.e7]

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Personalized Cancer Therapy: YES1 Is the New Kid on the Block.

Kunal Rai,

The key bottleneck for the continued success of precision medicine in cancer lies in identifying more targetable genes and associated efficacious clinically usable inhibitors. In this issue of Cancer Research, Hamanaka and colleagues identify YES1 kinase as a targetable cancer target and generate an effective chemical inhibitor for YES1 and ... Read more >>

Cancer Res. (Cancer research)
[2019, 79(22):5702-5703]

Cited: 1 time

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Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.

Chia-Wei Cheng, Moshe Biton, Adam L Haber, Nuray Gunduz, George Eng, Liam T Gaynor, Surya Tripathi, Gizem Calibasi-Kocal, Steffen Rickelt, Vincent L Butty, Marta Moreno-Serrano, Ameena M Iqbal, Khristian E Bauer-Rowe, Shinya Imada, Mehmet Sefa Ulutas, Constantine Mylonas, Mark T Whary, Stuart S Levine, Yasemin Basbinar, Richard O Hynes, Mari Mino-Kenudson, Vikram Deshpande, Laurie A Boyer, James G Fox, Christopher Terranova, Kunal Rai, Helen Piwnica-Worms, Maria M Mihaylova, Aviv Regev, Ömer H Yilmaz,

Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) ... Read more >>

Cell (Cell)
[2019, 178(5):1115-1131.e15]

Cited: 7 times

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Bivalent and Broad Chromatin Domains Regulate Pro-metastatic Drivers in Melanoma

Christopher Terranova, Ming Tang, Mayinuer Maitituoheti, Ayush Raman, Jonathan Schulz, Samir Amin, Elias Orouji, Katarzyna Tomczak, Sharmistha Sarkar, Junna Oba, Caitlin Creasy, Chang-Jiun Wu, Dongyu Zhao, Kaifu Chen, Lauren Haydu, Wei-Lien Wang, Alexander Lazar, Scott Woodman, Chantale Bernatchez, Kunal Rai,

ABSTRACT Chromatin deregulation is an emerging hallmark of cancer. However, the extent of epigenetic aberrations during tumorigenesis and their relationship with genetic aberrations are poorly understood. Using ChIP-sequencing for enhancers (H3K27ac and H3K4me1), promoters (H3K4me3), active transcription (H3K79me2) and polycomb (H3K27me3) or heterochromatin (H3K9me3) repression we generated chromatin state profiles ... Read more >>

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Gene-Specific Methylation Profiles for Integrative Methylation-Expression Analysis in Cancer Research

Yusha Liu, Keith Baggerly, Elias Orouji, Ganiraju Manyam, Huiqin Chen, Michael Lam, Jennifer Davis, Michael Lee, Bradley Broom, David Menter, Kunal Rai, Scott Kopetz, Jeffrey Morris,

Abstract DNA methylation is a key epigenetic factor regulating gene expression. While promoter-associated methylation has been extensively studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there ... Read more >>

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GENE-37. ATRX INACTIVATION DISRUPTS GLOBAL HETEROCHROMATIN LANDSCAPES AND ALTERS DISEASE-RELEVANT TRANSCRIPTIONAL ACTIVITY.

Carla Danussi, Anand K Singh, Grant Fischer, David J Picketts, Kasthuri Kannan, Kunal Rai, Jason T Huse,

AbstractDiffusely infiltrating gliomas feature loss-of function mutations in the SWI/SNF chromatin remodeler gene ATRX as defining molecular alterations delineating major adult and pediatric disease subtypes. So far, ATRX inactivation in cancer has been mainly correlated with alternative lengthening of telomeres, however, we recently reported that Atrx deficiency drives glioma-relevant phenotypes, ... Read more >>

Neuro-oncology (Neuro-oncology)
[2018, 20(Suppl 6):vi111-vi111]

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Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.

Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I Wistuba, Kunal Rai, Joseph Marszalek, P Andrew Futreal,

In the version of this article originally published, information regarding several funding sources was omitted from the Acknowledgements section. The following sentences should have been included: "This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the UT Lung ... Read more >>

Nat. Med. (Nature medicine)
[2018, 24(10):1627]

Cited: 1 time

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Super-enhancer impairment is a link between MLL4-inactivated lung tumors and their vulnerability to glycolysis pathway inhibition

Hunain Alam, Ming Tang, Mayinuer Maitituoheti, Shilpa Dhar, Samir Amin, Bingnan Gu, Tsai-Yu Chen, Yu-His Lin, Jichao Chen, Florian Muller, Francesco DeMayo, Laura Baseler, Kunal Rai, Min Gyu Lee,

Abstract Epigenetic modifiers often harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Here we show that lung-specific loss of the gene encoding the histone methyltransferase MLL4 (alias KMT2D; a COMPASS-like enzyme), which is ranked the most highly inactivated epigenetic modifier in lung cancer, strongly promotes ... Read more >>

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

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

SUMMARY Epigenetic modifiers have emerged as important regulators of tumor progression. We identified histone methyltransferase KMT2D as a potent tumor-suppressor through an in vivo epigenome-focused pooled RNAi screen in melanoma. KMT2D harbors frequent somatic point mutations in multiple tumor types. How these events contribute to tumorigenesis and whether they impart ... Read more >>

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KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.

R Tyler Hillman, Joseph Celestino, Christopher Terranova, Hannah C Beird, Curtis Gumbs, Latasha Little, Tri Nguyen, Rebecca Thornton, Samantha Tippen, Jianhua Zhang, Karen H Lu, David M Gershenson, Kunal Rai, Russell R Broaddus, P Andrew Futreal,

Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that ... Read more >>

Nat Commun (Nature communications)
[2018, 9(1):2496]

Cited: 4 times

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An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues.

Christopher Terranova, Ming Tang, Elias Orouji, Mayinuer Maitituoheti, Ayush Raman, Samirkumar Amin, Zhiyi Liu, Kunal Rai,

Histone modifications constitute a major component of the epigenome and play important regulatory roles in determining the transcriptional status of associated loci. In addition, the presence of specific modifications has been used to determine the position and identity non-coding functional elements such as enhancers. In recent years, chromatin immunoprecipitation followed ... Read more >>

J Vis Exp (Journal of visualized experiments : JoVE)
[2018, (134):]

Cited: 1 time

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Loss of histone acetylation and H3K4 methylation promotes melanocytic malignant transformation.

Ayush T Raman, Kunal Rai,

Epigenetic mechanisms play essential roles in biological processes such as cell maintenance, differentiation, proliferation and apoptosis. A recent report from our laboratory showed that the loss of histone acetylation and H3K4 (Histone H3 Lysine 4) methylation in the proximal regions of cancer regulatory genes promote tumorigenesis. ... Read more >>

(Molecular & cellular oncology)
[2018, 5(3):e1359229]

Cited: 1 time

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PRKCI promotes immune suppression in ovarian cancer.

Sharmistha Sarkar, Christopher A Bristow, Prasenjit Dey, Kunal Rai, Ruth Perets, Alejandra Ramirez-Cardenas, Shruti Malasi, Emmet Huang-Hobbs, Monika Haemmerle, Sherry Y Wu, Michael McGuire, Alexei Protopopov, Shan Jiang, Joyce F Liu, Michelle S Hirsch, Qing Chang, Alexander J Lazar, Anil K Sood, Ronny Drapkin, Ronald DePinho, Giulio Draetta, Lynda Chin,

A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-ι (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show ... Read more >>

Genes Dev. (Genes & development)
[2017, 31(11):1109-1121]

Cited: 11 times

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Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression.

Petko Fiziev, Kadir C Akdemir, John P Miller, Emily Z Keung, Neha S Samant, Sneha Sharma, Christopher A Natale, Christopher J Terranova, Mayinuer Maitituoheti, Samirkumar B Amin, Emmanuel Martinez-Ledesma, Mayura Dhamdhere, Jacob B Axelrad, Amiksha Shah, Christine S Cheng, Harshad Mahadeshwar, Sahil Seth, Michelle C Barton, Alexei Protopopov, Kenneth Y Tsai, Michael A Davies, Benjamin A Garcia, Ido Amit, Lynda Chin, Jason Ernst, Kunal Rai,

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions ... Read more >>

Cell Rep (Cell reports)
[2017, 19(4):875-889]

Cited: 23 times

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Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.

Yonathan Lissanu Deribe, Yanxia Shi, Kunal Rai, Luigi Nezi, Samir B Amin, Chia-Chin Wu, Kadir C Akdemir, Mozhdeh Mahdavi, Qian Peng, Qing Edward Chang, Kirsti Hornigold, Stefan T Arold, Heidi C E Welch, Levi A Garraway, Lynda Chin,

PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By ... Read more >>

Proc. Natl. Acad. Sci. U.S.A. (Proceedings of the National Academy of Sciences of the United States of America)
[2016, 113(9):E1296-305]

Cited: 24 times

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Genomic Classification of Cutaneous Melanoma.

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We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, ... Read more >>

Cell (Cell)
[2015, 161(7):1681-1696]

Cited: 803 times

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H3K9me3-mediated repression of KLF6: Discovering a novel tumor suppressor in liposarcoma using a systematic epigenomic approach.

Emily Z Keung, Kunal Rai,

The pathogenesis of well-differentiated and dedifferentiated liposarcoma is poorly understood. We recently reported Kruppel-like factor 6 (KLF6) as a histone H3 lysine 9 trimethyl (H3K9me3)-regulated and differentially expressed transcription factor serving a previously unappreciated tumor suppressor role in liposarcoma. Mechanistically, KLF6 may drive adipocytic differentiation through increased expression of known ... Read more >>

(Molecular & cellular oncology)
[2016, 3(3):e1093691]

Cited: 1 time

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Dual Roles of RNF2 in Melanoma Progression.

Kunal Rai, Kadir C Akdemir, Lawrence N Kwong, Petko Fiziev, Chang-Jiun Wu, Emily Z Keung, Sneha Sharma, Neha S Samant, Maura Williams, Jacob B Axelrad, Amiksha Shah, Dong Yang, Elizabeth A Grimm, Michelle C Barton, Denai R Milton, Timothy P Heffernan, James W Horner, Suhendan Ekmekcioglu, Alexander J Lazar, Jason Ernst, Lynda Chin,

UNLABELLED:Epigenetic regulators have emerged as critical factors governing the biology of cancer. Here, in the context of melanoma, we show that RNF2 is prognostic, exhibiting progression-correlated expression in human melanocytic neoplasms. Through a series of complementary gain-of-function and loss-of-function studies in mouse and human systems, we establish that RNF2 is ... Read more >>

Cancer Discov (Cancer discovery)
[2015, 5(12):1314-1327]

Cited: 25 times

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DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC.

Kunal Rai, Sharmistha Sarkar, Talmage J Broadbent, Matthew Voas, Kenneth F Grossmann, Lincoln D Nadauld, Somaye Dehghanizadeh, Fanuel T Hagos, Yumei Li, Rachel K Toth, Stephanie Chidester, Timothy M Bahr, W Evan Johnson, Brad Sklow, Randall Burt, Bradley R Cairns, David A Jones,

Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells ... Read more >>

Cell (Cell)
[2010, 142(6):930-942]

Cited: 49 times

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