4. Discussion
The present study provided the initial evidence that DOT1L was required
for the proper proliferation of B lymphoma cells, and Dex could
downregulate DOT1L expression. Such downregulation role may be a novel
mechanism for Dex to treat B lymphoma.
Aberrant post-translational modifications play a pivotal role in cancer
biology and cancer therapy [22-25], one of which is the histone
methylation involved in cell cycle and somatic reprogramming
[26-28]. DOT1L is the sole methyltransferase capable of catalyzing
the methylation of histone H3 at lysine 79 that is considered to involve
in the development of plenty of tumors.
For instance, hypermethylation of
H3K79 by DOT1L is crucial for the onset of MLL-rearranged leukemia
[29] and high level of DOT1L serves as the marker of poor prognosis
in renal clear cell carcinoma [30] and ovarian cancer cells
[15]. Downregulation of DOT1L induces a G1 arrest and
cellular senescence in lung cancer cells [13] and
inhibition
of DOT1L suppresses the proliferation, self-renewal, and metastasis of
breast cancer cells [14]. The aboved evidences demonstrate that
DOT1L may be a novel therapeutic target in cancer treatment. This study
showed that DOT1L was highly expressed in B lymphoma cells and
silencing DOT1L inhibited the growth of B lymphoma cells. To
date, this is the first report to reveal the oncogenic role of DOT1L in
lymphoma. How DOT1L promotes the growth of B cell lymphoma needs further
study.
Dex plays a central role in B lymphoma therapy and it commonly displays
its anti-cancer efficacy via activating GR [31, 32]. GR functions
mainly in three manners: Firstly, GR binds directly to DNA to regulate
gene expression, such as GR binding to the GRE of SARI promoter sequence
to upregulate its mRNA level [33]; Secondly, GR is tethered to other
transcription factors such as STAT3 and NF-κB to affect gene expression;
Thirdly, GR binds to DNA and then they coordinate with adjacent
DNA-binding transcription factors [34]. In our study, we found that
Dex
downregulatedDOT1L in a GR-dependent manner. However, DOT1L was not a
direct target gene of GR because GR did not suppress the activity ofDOT1L promoter region (-1,800 bp to +200 bp). Furthermore, we
found that Dex reduced the mRNA level of DOT1L through decreasing
its mRNA stability. Since RNA binding proteins or microRNAs play an
significant role in regulating the mRNA stability [35-37], the
relevant RNA binding proteins or microRNAs that may mediate the effect
of Dex on DOT1L requires further investigation.
Most researchers have concentrated on the way that protein-protein
interactions influence DOT1L activity, however, the upstream mechanisms
that regulate DOT1L remain largely unknown. A recent study reported that
CBP stabilized DOT1L in protein level by inducing DOT1L acetylation to
facilitate CRC progression and metastasis [38]. Another study showed
that N-Myc bond to the promoter region of DOT1L to upregulateDOT1L . Silencing DOT1L decreased the expression ofOCD1 and E2F2 (two target gene of N-Myc) and suppressed
the growth of neuroblastoma cells [16]. Our study showed that GR, an
important transcription factor, was a novel upstream regulator ofDOT1L . Interestingly, Myc rearrangement plays an pivotal role in
the B lymphoma cells [39, 40]. It is of great interest to explore
whether Myc rearrangement can link to the high levels of DOT1L in
B lymphoma cells.
In conclusion, our study revealed that DOT1L is an oncogene even
a new marker for therapy in B lymphoma cells. Downregulation of DOT1L
mRNA stability by Dex may be an important mechanism for Dex to kill B
lymphoma cells. Therefore, inhibition of DOT1L/H3K79 could be novel
probes for clinically useful therapeutics in B lymphoma.