Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

Shi, Wenna; Cui, Shu‐Xiang; Song, Zhiyu; Wang, Shuqing; Sun, Shengzhi; Yu, Xinfeng; Li, Ye; Zhang, Yuhang; Gao, Zu–Hua; Qu, Xian‐Jun

doi:10.18632/oncotarget.17174

Cited by 24 publications

(17 citation statements)

References 43 publications

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“…TCGA gene expression analysis revealed ER + breast cancer patients had elevated SphK2 transcripts compared to matched controls ( Figure 6A). SphK2 expression is also found elevated in other human cancers including NSCLC, 52 and colon cancer, 51 with targeting SphK2 with a selective inhibitor reducing lung cancer growth, 76 papillary thyroid carcinoma, 77 bladder cancer, 78 colorectal cancer, 79 and colon cancer, 80 with just one exception, 81 indicating SphK2 is a potentially good therapeutic target. 65 Our previous work also revealed SphK2/ S1P is essential for metastatic breast cancer cell growth and survival.…”

Section: Discussionmentioning

confidence: 99%

“…Sphingosine kinase 2 expression has been found elevated in both colon cancer 51 and non-small cell lung cancer F I G U R E 5 SphK2 enhances HIF-1α binding to the VEGF promoter. MCF-7 cells (A, B) or MDA-MB-231 cells (C) transfected with siControl or siSphK2 were exposed to hypoxia (black bar) or normoxia (white bar) for 40 minutes.…”

Section: Analysis Of Expression Levels Of Sphk2 and Hif-1α In Humanmentioning

confidence: 99%

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Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Hait

Maiti

et al. 2020

FASEB j.

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Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine‐1‐phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia‐responsive master transcription factors hypoxia‐inducible factor (HIF)‐1α/2α, and their functions in breast cancer, with a focus on triple‐negative breast cancer (TNBC). We have shown SphK2 is associated with HIF‐1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF‐1α. SphK2, and HIF‐1α expression levels are elevated in metastatic estrogen receptor‐positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K‐145, that nuclear S1P, histone acetylation, HIF‐1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF‐1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Expression Levels Of Sphk2 and Hif-1α In Humanmentioning

confidence: 99%

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Hait

Maiti

et al. 2020

FASEB j.

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“…Indeed, sphingosine kinase 2 (SphK2) over-expression was found in colonic cancer cells resistant to retinoic acids [126]. The SphK2 mechanism of action induced the increase of RXRα translocation into the cytoplasm and then the rapidly degradation through the polyubiquitination pathway, so inhibiting the triggering of apoptosis (Figure 3) [127].…”

Section: Escape Routes From Apoptosismentioning

confidence: 99%

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Costantini

Molinari

Farinon

et al. 2020

JCM

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Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

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“…In agreement with this eventuality, studies have suggested that, when SphK2 is localized in the nucleus, it can inhibit the synthesis of DNA, thus exerting anti-proliferative effects ( Hait et al, 2009 ). Conversely, other contributions have shown that, in human colon carcinoma cells, S1P generated by nuclear SphK2 can inhibit the retinoic acid receptor β, attenuating the tumor suppressor effects of this receptor ( Shi et al, 2017 ).…”

Section: Structure and Function Of Sphingosine Kinasesmentioning

confidence: 99%

Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System

et al. 2017

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The sphingosine kinases 1 and 2 (SphK1 and 2) catalyze the phosphorylation of the lipid, sphingosine, generating the signal transmitter, sphingosine 1-phosphate (S1P). The activation of such kinases and the subsequent S1P generation and secretion in the blood serum of mammals represent a major checkpoint in many cellular signaling cascades. In fact, activating the SphK/S1P system is critical for cell motility and proliferation, cytoskeletal organization, cell growth, survival, and response to stress. In the cardiovascular system, the physiological effects of S1P intervene through the binding and activation of a family of five highly selective G protein-coupled receptors, called S1PR1-5. Importantly, SphK/S1P signal is present on both vascular and myocardial cells. S1P is a well-recognized survival factor in many tissues. Therefore, it is not surprising that the last two decades have seen a flourishing of interest and investigative efforts directed to obtain additional mechanistic insights into the signaling, as well as the biological activity of this phospholipid, and of its receptors, especially in the cardiovascular system. Here, we will provide an up-to-date account on the structure and function of sphingosine kinases, discussing the generation, release, and function of S1P. Keeping the bull’s eye on the cardiovascular system, we will review the structure and signaling cascades and biological actions emanating from the stimulation of different S1P receptors. We will end this article with a summary of the most recent, experimental and clinical observations targeting S1PRs and SphKs as possible new therapeutic avenues for cardiovascular disorders, such as heart failure.

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Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

Cited by 24 publications

References 43 publications

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System

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