SUMOylated MAFB promotes colorectal cancer tumorigenesis.

Lin-Sen Yang,Yin-Yin Xie,Xiao-Jian Zhang,Qiu-Hua Huang,Xiao-Jian Sun,Ren Zhao

doi:10.18632/oncotarget.13129

Lin-Sen Yang, Yin-Yin Xie + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.13129

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Journal: Oncotarget	Publication Date: Nov 5, 2016
Citations: 23	License type: cc-by

Affiliation: Shanghai Jiao Tong University

Abstract

The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment.

Highlights

In spite of advancements in treatment options, including surgical resection, radiotherapy, immunotherapy and chemotherapy, colorectal cancer (CRC) remains the third most common cancer globally, with the fourth highest mortality rate [1, 2]
Altered musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro
We studied the status of MAFB in The Cancer Genome Atlas (TCGA) and found aberrant MAFB amplification in a majority of enrolled tumor types (Figure 1A)

Summary

Introduction

In spite of advancements in treatment options, including surgical resection, radiotherapy, immunotherapy and chemotherapy, colorectal cancer (CRC) remains the third most common cancer globally, with the fourth highest mortality rate [1, 2]. About 50% percent of CRC patients experience multiple relapses and die within five years of diagnosis [3]. The tumor node metastasis (TNM) staging system is currently the most important guideline in CRC therapeutic regimen selection and prognosis prediction [4]. Patients with the same CRC stage may have different pathological processes and prognoses. To improve upon existing treatment and prognostic options, the molecular mechanisms driving CRC must be better understood. Specific CRC biomarkers would allow for more accurate predictions of patient responses to specific treatments, potentially improving survival outcomes [5]

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