[Frontiers in Bioscience, Landmark, 25, 781-797, Jan 1, 2020]

SETD2, an epigenetic tumor suppressor: a focused review on GI tumor

Ming Hu1, Mu Hu2, Qin Zhang3, Jin-ping Lai4, Xiu-li Liu1

1Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA, 2Department of Orthopaedics, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, Shanghai, China, 3Department of Pathology, Third Central Hospital of Nankai University, Tianjin, China, 4Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The tumor suppressor function of SETD2 in gastrointestinal cancer
    3.1. Regulation of SETD2 expression level in GI tumors
    3.2. SETD2 mutations in GI tumors
4. Potential mechanism of SETD2 regulating GI tumor progression
    4.1. SETD2 and gene transcription
    4.2. SETD2 and mRNA splicing
    4.3. SETD2 and DNA replication stress
    4.4. SETD2 and DNA damage repair
    4.5. SETD2 regulation of mitosis by tubulin methylation
    4.6. SETD2 and immune deregulation
    4.7. SETD2 and chemoresistance
5. Conclusion and perspectives
6. Acknowledgments
7. References

1. ABSTRACT

Significant progress has been made in our understanding of the role of epigenetic modifiers in many types of human cancer. Here, we review currently available studies on the unique histone methyltransferase, SETD2, which is responsible for H3 lysine 36 tri-methylation (H3K36me3). SETD2 plays pivotal roles in RNA alternative splicing regulation, DNA damage repair, and cytoskeleton protein methylation; inactivation of SETD2 and resultant dysregulation of these functions may lead to tumorigenesis. Despite being a newly discovered tumor suppressor, SETD2 has been found to be mutated in multiple types of cancer, including gastrointestinal tumor. Some tumors can acquire a selective growth advantage after SETD2 inactivation, which could happen in different stages in tumor progression. Decreased level of H3K36me3 caused by SETD2 inactivation has been shown to associate with higher tumor grade, tumor stage, metastasis risk, and shorter survival. Some studies also suggest that SETD2 mutation is associated with therapy resistance, therefore these SETD2-deficient tumors may need different therapeutic strategies.

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Key Words: SETD2, H3K36me3, RNA Alternative Splicing, Tubulin Methylation, DNA Damage Repair, Progression and Prognostic biomarker, Review

Send correspondence to: Xiuli Liu, Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA, Tel: 352-265-7977, Fax: 352-627-9242, E-mail: xiuliliu@ufl.edu