Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Abstract

Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (Myb Plt4 ) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1-driven tumor growth. Here, it was found that Myb/ MYB and Ccne1/CCNE1 expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)-mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the Ccne1 promoter and regulated its endogenous expression. In contrast, Myb Plt4 served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. Myb Plt4/Plt4 mice died prematurely on an Apc Min/þ background associated with hematopoietic defects, including a myelodysplasia; nevertheless, Apc Min/þ mice were protected from intestinal tumorigenesis when crossed to Myb Plt4/þ mice. Knockdown of CCNE1 transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer.Implications: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. Mol Cancer Res; 13(8); 1185-96. Ó2015 AACR.

MYB is a novel regulator of pancreatic tumour growth and metastasis

“…In the present study, our data revealed the essential role of MYB in promoting the growth of PC cells under in vitro as well as in orthotopic tumour xenograft mouse model. Similar observations have also been made in other studies ( Melani et al , 1991 ; Ye et al , 2014 ; Cheasley et al , 2015 ; Wang et al , 2015 ). Blocking the function of MYB by antisense oligonucleotides or its dominant-negative forms led to the suppression of proliferation and survival in acute myeloid leukemia and chronic myeloid leukemia ( Jahagirdar et al , 2001 ; Pattabiraman and Gonda, 2013 ).…”

“…Similarly, in our recently published study, we reported that overexpression of MYB promoted, whereas its knockdown inhibited, the growth of prostate cancer cells ( Srivastava et al , 2012 ). More recently, Cheasley et al (2015) demonstrated that defective MYB function perturbs colorectal tumorigenesis in mouse model. Furthermore, an overexpression of MYB was also reported in nasopharyngeal carcinoma (NPC), which was associated with the growth of NPC cells ( Wang et al , 2015 ).…”

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma

“…The results demonstrated that upregulation of MYB increased the relative number of cells, which was consistent with previous findings in prostate and pancreatic cancer (37,38). Knockdown of MYB significantly inhibited cell proliferation, which was similar to findings for acute myeloid leukaemia, chronic myeloid leukaemia and colon cancer (39,40). Mechanistically, previous studies demonstrated that MYB induced the growth of tumour cells through the promotion of cell cycle progression, which was associated with cell proliferation (41,42).…”

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

“…This G1/S and G2/M cell cycle arrest is mediated through downregulation of cyclin E1 during G1/S transition (Ohtsubo et al, 1995, Malaterre et al, 2007, Cheasley et al, 2015 and cyclin B1 during G2/M transition (Nakata et al, 2007). Furthermore, five DNA damaging agents (ETO, cisplatin, doxorubicin, mitomycin C and hydroxyurea) cause S phase delay and G2/M phase arrest (Smith et al, 1994, Ling et al, 1996, Johnson et al, 1999, Kang et al, 2001, Nam et al, 2010.…”

“…Previous studies indicated that MYB knockdown inhibits cell proliferation and leads to cell cycle arrest at the late G1 or early S phase (Drabsch et al, 2007) via downregulation of cyclin B1 expression (Okada et al, 2002, Nakata et al, 2007 and cyclin E1 (Malaterre et al, 2007, Cheasley et al, 2015. MYB overexpression promotes cell cycle progression and cell proliferation through upregulation of cyclins (A1, D1 and E1) (Srivastava et al, 2012).…”