HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells.
B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.|Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Zhen
Z
Tan
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Quan
Q
Huang
Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Jia
J
Zang
Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Shi-Feng
SF
Teng
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Tian-Rui
TR
Chen
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Hai-Feng
HF
Wei
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Dian-Wen
DW
Song
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Tie-Long
TL
Liu
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Xing-Hai
XH
Yang
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Chuan-Gang
CG
Fu
Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Zhi-Qian
ZQ
Hu
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Wang
W
Zhou
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Wang-Jun
WJ
Yan
Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Jian-Ru
JR
Xiao
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D020218:Response Elements; D014157:Transcription Factors; D015533:Transcriptional Activation
C111180:BCL9 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D014157:Transcription Factors
B-cell CLL/lymphoma 9 protein; colorectal cancer; hypoxia; hypoxia inducible factors-1α