KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation

Yang Fang; Dan Zhang; Tingting Hu; Hongyan Zhao; Xuan Zhao; Zhefeng Lou; Yongshan He; Wenzheng Qin; Jianfu Xia; Xiaohua Zhang; Le-Chi Ye

doi:10.1002/cam4.2226

KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation

Cancer Med. 2019 Jul;8(7):3544-3552. doi: 10.1002/cam4.2226. Epub 2019 May 15.

Authors

Yang Fang^{1

2}, Dan Zhang³, Tingting Hu⁴, Hongyan Zhao^{1

2}, Xuan Zhao^{1

2}, Zhefeng Lou^{1

2}, Yongshan He⁵, Wenzheng Qin⁶, Jianfu Xia⁷, Xiaohua Zhang⁸, Le-Chi Ye⁸

Affiliations

¹ Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, China.
² School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
³ Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai, China.
⁷ Department of General Surgery, Wenzhou Central Hospital, Wenzhou, China.
⁸ Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

Accumulating evidence supports the notion that epigenetic modifiers are abnormal in carcinogenesis and have a fundamental role in cancer progression. Among these aberrant epigenetic modifiers, the function of histone methyltransferase KMT2A in somatic tumors is not well known. By analyzing KMT2A expression in patient tissues, we demonstrated that KMT2A was overexpressed in colorectal cancer tissues in comparison with adjacent normal tissues and its expression was positively correlated with cancer stages. In KMT2A-knockdown HCT116 and DLD1 cells, cell invasion and migration were consequently suppressed. In addition, KMT2A depletion effectively suppressed cancer metastasis in vivo. Mechanistically, cathepsin Z (CTSZ) was demonstrated to be an important downstream gene of KMT2A. Further studies showed that p65 could recruit KMT2A on the promoter region of the downstream gene CTSZ and knockdown of p65 could reduce the KMT2A on the promoter of CTSZ. Finally, our present study revealed that KMT2A epigenetically promotes cancer progression by targeting CTSZ, which has specific functions in cancer invasion and metastasis.

Keywords: CTSZ; KMT2A; cancer development; epigenetic modifier.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cathepsin Z / genetics*
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism*
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism*
Disease Models, Animal
Epigenomics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Immunohistochemistry
Mice
Models, Biological
Myeloid-Lymphoid Leukemia Protein / metabolism*
Protein Binding
Transcriptional Activation*
Xenograft Model Antitumor Assays

Substances

KMT2A protein, human
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
CTSZ protein, human
Cathepsin Z