Dr. Hu Guohong’s research group at the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, demonstrated the pivotal function of Metadherin (MTDH) in cancer stem cell maintenance and revealed the epigenetic regulation of MTDH to its downstream gene TWIST1.

Cancer stem-like cells (CSCs) are defined as a subpopulation of tumor cells with self-renewal and differentiation abilities. Recent studies reveal that cancer stem-like cells can re-initiate tumors, resist chemo-therapy and give rise to metastases.

Metadherin (MTDH) has been identified to play critical roles in many aspects of cancer processes including tumor growth, drug resistance, relapse and metastasis. However, little is known about the molecular mechanism of MTDH in cancer.

Graduate students Liang Yajun and Hu Jing in the research group led by Professor Hu Guohong, demonstrated that MTDH's pluripotency in cancer might be due to its fundamental role in driving CSC expansion and define TWIST1, a basic helix-loop-helix transcription factor critical for cancer cell stemness and metastasis, as a downstream mediator of the process. MTDH upregulated the transcription level of TWIST1. Overexpression of TWIST1 in MTDH knockdown cells rescued the anti-tumorigenicity phenotype of MTDH inhibition.

Moreover, the study showed that MTDH activated TWIST1 expression indirectly by facilitating H3 Histone acetylation in its promoter, a process mediated by the histone acetyltransferase CBP. MTDH interacted with CBP and prevented its ubiquitylation-dependent degradation, resulting in the epigenetic activation of TWIST1.

More importantly, MTDH’s level is positively correlated to the CSC abundance and the expression of TWIST1 in breast tumor samples.

Overall, the study reveals that MTDH promotes CSC accumulation and breast tumorigenicity by regulating TWIST1, deepening the understanding of MTDH function in cancer.

In addition, as histone modification inhibitors are being actively pursued in therapeutics, these findings that link MTDH to epigenetic regulation may provide new opportunities to target CSC and MTDH signaling in metastatic cancer.

The paper entitled “Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem-Like Cell Traits in Breast Cancer” was published online in Journal of Cancer Research on July 3, 2015.

Contact: 

Hu Guohong

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 

Shanghai 200031, China

Phone: 86-21-54923296;  

E-mail: ghhu@sibs.ac.cn