Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1

Qu Deng; Ramakrishnan Natesan; Florencia Cidre-Aranaz; Shehbeel Arif; Ying Liu; Reyaz Ur Rasool; Pei Wang; Erick Mitchell-Velasquez; Chandan Kanta Das; Endrit Vinca; Zvi Cramer; Patrick J Grohar; Margaret Chou; Chandan Kumar-Sinha; Kristy Weber; T S Karin Eisinger-Mathason; Nicolas Grillet; Thomas G. P. Grünewald; Irfan A Asangani

doi:10.1016/j.celrep.2022.110971

Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1

Cell Rep. 2022 Jun 14;39(11):110971. doi: 10.1016/j.celrep.2022.110971.

Authors

Qu Deng¹, Ramakrishnan Natesan¹, Florencia Cidre-Aranaz², Shehbeel Arif¹, Ying Liu³, Reyaz Ur Rasool¹, Pei Wang⁴, Erick Mitchell-Velasquez¹, Chandan Kanta Das¹, Endrit Vinca⁵, Zvi Cramer¹, Patrick J Grohar⁶, Margaret Chou³, Chandan Kumar-Sinha⁷, Kristy Weber⁸, T S Karin Eisinger-Mathason⁹, Nicolas Grillet⁴, Thomas G. P. Grünewald¹⁰, Irfan A Asangani¹¹

Affiliations

¹ Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
² Max-Eder Research Group of Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
³ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, PA, USA.
⁴ Department of Otolaryngology-Head & Neck Surgery, School of Medicine, Stanford University, Stanford, CA, USA.
⁵ Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Hopp Children's Cancer Center (KiTZ), Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁶ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Max-Eder Research Group of Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹¹ Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: asangani@upenn.edu.

Abstract

Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.

Keywords: CP: Cancer; CP: Molecular biology; EWSR1::FLI1; Ewing sarcoma; LOXHD1; biomarker; enhancer; hypoxia; integrative genomics; metastasis; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Carrier Proteins* / genetics
Cell Line, Tumor
Child
Enhancer Elements, Genetic*
Gene Expression Regulation, Neoplastic
Humans
Oncogene Proteins, Fusion* / genetics
Oncogene Proteins, Fusion* / metabolism
Proteins / metabolism
Proto-Oncogene Protein c-fli-1 / genetics
Proto-Oncogene Protein c-fli-1 / metabolism
RNA-Binding Protein EWS / genetics
RNA-Binding Protein EWS / metabolism
Sarcoma, Ewing* / genetics
Sarcoma, Ewing* / pathology

Substances

Carrier Proteins
LOXHD1 protein, human
Oncogene Proteins, Fusion
Proteins
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS

Abstract

Publication types

MeSH terms

Substances

Grants and funding