Rajendran Praveen, Dashwood Wan-Mohaiza, Li Li, Kang Yuki, Kim Eunah, Johnson Gavin, Fischer Kay A, Löhr Christiane V, Williams David E, Ho Emily, Yamamoto Masayuki, Lieberman David A, Dashwood Roderick H
Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR USA.
Clin Epigenetics. 2015 Sep 18;7(1):102. doi: 10.1186/s13148-015-0132-y. eCollection 2015.
The dietary agent sulforaphane (SFN) has been reported to induce nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)-dependent pathways as well as inhibiting histone deacetylase (HDAC) activity. The current investigation sought to examine the relationships between Nrf2 status and HDAC expression in preclinical and translational studies.
Wild type (WT) and Nrf2-deficient (Nrf2(-/+)) mice were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH) followed by 400 ppm SFN in the diet (n = 35 mice/group). WT mice were more susceptible than Nrf2(-/+) mice to tumor induction in the colon. Tumors from WT mice had higher HDAC levels globally and locally on genes such as cyclin-dependant kinase inhibitor 2a (Cdkn2a/p16) that were dysregulated during tumor development. The average tumor burden was reduced by SFN from 62.7 to 26.0 mm(3) in WT mice and from 14.6 to 11.7 mm(3) in Nrf2(-/+) mice. The decreased antitumor activity of SFN in Nrf2(-/+) mice coincided with attenuated Cdkn2a promoter interactions involving HDAC3. HDAC3 knockdown in human colon cancer cells recapitulated the effects of SFN on p16 induction. Human subjects given a broccoli sprout extract supplement (200 μmol SFN equivalents), or reporting more than five cruciferous vegetable servings per week, had increased p16 expression that was inversely associated with HDAC3 in circulating peripheral blood mononuclear cells (PBMCs) and in biopsies obtained during screening colonoscopy.
Nrf2 expression varies widely in both normal human colon and human colon cancers and likely contributes to the overall rate of tumor growth in the large intestine. It remains to be determined whether this influences global HDAC protein expression levels, as well as local HDAC interactions on genes dysregulated during human colon tumor development. If corroborated in future studies, Nrf2 status might serve as a biomarker of HDAC inhibitor efficacy in clinical trials using single agent or combination modalities to slow, halt, or regress the progression to later stages of solid tumors and hematological malignancies.
膳食因子萝卜硫素（SFN）已被报道可诱导核因子红细胞2（NF-E2）相关因子2（Nrf2）依赖性通路，并抑制组蛋白脱乙酰基酶（HDAC）活性。本研究旨在通过临床前和转化研究来探究Nrf2状态与HDAC表达之间的关系。
野生型（WT）和Nrf2基因缺陷型（Nrf2(-/+)）小鼠先用结肠致癌物1,2-二甲基肼（DMH）处理，随后在饮食中给予400 ppm的SFN（每组n = 35只小鼠）。WT小鼠比Nrf2(-/+)小鼠更容易在结肠诱发肿瘤。WT小鼠的肿瘤在整体和局部的HDAC水平均较高，这些HDAC存在于肿瘤发生过程中失调的基因上，如细胞周期蛋白依赖性激酶抑制剂2a（Cdkn2a/p16）。在WT小鼠中，SFN使平均肿瘤负荷从62.7降至26.0立方毫米，在Nrf2(-/+)小鼠中从14.6降至11.7立方毫米。SFN在Nrf2(-/+)小鼠中抗肿瘤活性的降低与涉及HDAC3的Cdkn2a启动子相互作用减弱相吻合。在人结肠癌细胞中敲低HDAC3可重现SFN对p16诱导的作用。给予西兰花芽提取物补充剂（200 μmol SFN当量）或每周食用超过五份十字花科蔬菜的人类受试者，其p16表达增加，且与循环外周血单核细胞（PBMC）和结肠镜筛查活检组织中的HDAC3呈负相关。
Nrf2表达在正常人类结肠和人类结肠癌中差异很大，可能对大肠肿瘤的总体生长速率有影响。Nrf2是否影响整体HDAC蛋白表达水平以及人类结肠肿瘤发生过程中失调基因上的局部HDAC相互作用，仍有待确定。如果在未来研究中得到证实，Nrf2状态可能作为HDAC抑制剂疗效的生物标志物，用于临床试验中采用单一药物或联合治疗方式来延缓、阻止或逆转实体瘤和血液系统恶性肿瘤进展至晚期阶段。
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