Breakdown of ‘protective mechanisms’ can drive lung cancer development
June 22, 2023
GRAND RAPIDS, Mich. (June 22, 2023) — Loss of two key “protector” proteins initiates epigenetic changes that transform healthy lung cells into cancerous ones, according to new research from Van Andel Institute scientists.
The findings, published in Cancer Research, are among the first to demonstrate a wholly epigenetic origin for cancer cells and may have implications for future cancer treatment and prevention strategies.
“Our findings shed new light on the importance of epigenetics in cancer development,” said Gerd Pfeifer, Ph.D., a VAI professor and senior study author. “In theory, it is easier to target epigenetics than genetics in cancer treatment, which opens new possibilities for therapeutic development.”
Cancers largely arise from mutations to the DNA sequence, which disrupts the genetic instructions required for normal function. The resulting errors allow malignant cells to flourish and spread, crowding out healthy cells and causing illness.
Since the 1980s, however, scientists have recognized the role of another critical regulatory system in cancer development: epigenetics.
Epigenetic mechanisms govern whether genes are “on” or “off” by adding or removing chemical tags called methyl groups. Inappropriate methylation wreaks havoc by activating or silencing genes at the wrong time; for example, a gene that regulates cell death may be erroneously switched off, allowing cancerous cells to replicate unchecked.
Although epigenetic mechanisms are now recognized as central players in cancer, exactly how these processes work has remained unclear.
To find answers, Pfeifer and his colleagues focused on two proteins that protect more than 4,000 genes from inappropriate methylation: TET and RYBP.
Their research, which was conducted in lab models of lung cancer, revealed that loss of either TET or RYBP on their own has only minimal to
moderate impact. Loss of both, however, leads to widespread aberrant methylation — and, subsequently, cancer.
Their findings suggest the combination of RYBP and TET is crucial to preserving normal function. RYBP helps maintain a massive protein complex called PRC1, which shields thousands of genes from methylation. TET proteins protect the genome by removing methylation when it is not appropriate. When these protective mechanisms break down in tandem, methylation spins out of control.
Going forward, Pfeifer plans to explore this process in other cancer types to investigate whether it’s a phenomenon restricted to lung cells or if it has wider applicability. If the combined loss of RYBP and TET in other cell types has the same result, it could have broad implications for our understanding of cancer and development of new therapies.
Authors include Wei Cui, Ph.D., Zhijun Huang, Ph.D., Seung-Gi Jin, Ph.D., Jennifer Johnson, M.S., Kin H. Lau, Ph.D., and Galen Hostetter, M.D., of VAI. VAI’s Genomics Core, Pathology and Biorepository Core, Optical Imaging Core and Vivarium Core also contributed to this work.
Research reported in this publication was supported by Van Andel Institute and the National Cancer Institute of the National Institutes of Health under award no. R01CA234595 (Pfeifer). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Banner image credit: Courtesy of Adobe Stock — catalin.
ABOUT VAN ANDEL INSTITUTE
Van Andel Institute (VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting-edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to nearly 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K-12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology.
Uharibifu wa mifumo ya kinga inaweza kuendesha maendeleo ya saratani ya mapafu Juni 22, 2023 - Grand Rapids, Mich. - Kupoteza protini mbili muhimu za mlinzi huanzisha mabadiliko ya epigenetic ambayo hubadilisha seli za mapafu zenye afya kuwa saratani, kulingana na utafiti mpya kutoka kwa wanasayansi wa Taasisi ya Van Andel. Matokeo ya utafiti huo, yaliyochapishwa katika jarida la Cancer Research, ni miongoni mwa matokeo ya kwanza kuonyesha asili ya epigenetic kabisa kwa seli za saratani na inaweza kuwa na athari kwa matibabu ya saratani ya baadaye na mikakati ya kuzuia. "Ugunduzi wetu unatoa mwangaza mpya juu ya umuhimu wa epigenetics katika maendeleo ya kansa", alisema Gerd Pfeifer, Ph.D., profesa wa VAI na mwandishi mwandamizi wa utafiti. "Kwa nadharia, ni rahisi kulenga epigenetics kuliko urithi katika matibabu ya kansa, ambayo inafungua uwezekano mpya wa maendeleo ya matibabu. ""Kansa kwa kiasi kikubwa hutokea kutokana na mabadiliko ya mfululizo wa DNA, ambayo huvuruga maagizo ya maumbile yanayohitajika kwa kazi ya kawaida." Makosa yanayotokana na hilo huruhusu chembe mbaya kusitawi na kuenea, zikizidisha chembe zenye afya na kusababisha ugonjwa. Tangu miaka ya 1980, wanasayansi wamegundua jukumu la mfumo mwingine muhimu wa udhibiti katika maendeleo ya kansa: epigenetics. Utaratibu wa epigenetic huamua kama jeni ni <unk>on<unk> au <unk>off<unk> kwa kuongeza au kuondoa vitambulisho vya kemikali vinavyoitwa vikundi vya methyl. Methylation isiyofaa husababisha uharibifu kwa kuamsha au kusimamisha jeni wakati usiofaa; kwa mfano, jeni inayodhibiti kifo cha seli inaweza kuzimwa kimakosa, ikiruhusu seli za kansa kuiga bila kudhibitiwa. Ingawa sasa utaratibu wa epigenetic unatambuliwa kuwa sehemu muhimu ya kansa, bado haijulikani wazi jinsi utaratibu huo unavyofanya kazi. Pfeifer na wenzake walichunguza protini mbili ambazo huzuia jeni zaidi ya 4,000 zisifanyike methylation. Utafiti wao, uliofanywa katika mifano ya maabara ya saratani ya mapafu, ulifunua kwamba kupoteza TET au RYBP peke yake kuna athari ndogo tu hadi ya wastani. Hata hivyo, kupoteza zote mbili husababisha methylation ya ajabu iliyoenea sana <unk> na, baadaye, kansa. Matokeo ya utafiti huo yanaonyesha kwamba mchanganyiko wa RYBP na TET ni muhimu kwa kuhifadhi utendaji wa kawaida. RYBP inasaidia kudumisha protini kubwa inayoitwa PRC1, ambayo inalinda maelfu ya jeni kutoka kwa methylation. TET protini kulinda genome kwa kuondoa methylation wakati si sahihi. Mifumo hiyo ya ulinzi inapovunjika pamoja, methylation huanza kuharibika. Kuendelea, Pfeifer anapanga kuchunguza mchakato huu katika aina nyingine za kansa kuchunguza kama ni jambo lililopunguzwa kwa seli za mapafu au kama ina matumizi pana. Ikiwa kupoteza pamoja kwa RYBP na TET katika aina nyingine za seli kuna matokeo sawa, inaweza kuwa na athari kubwa kwa uelewa wetu wa saratani na maendeleo ya matibabu mapya. "Wanahusika ni Wei Qi, Ph.D., Zhijun Huang, Ph.D., Seung-Jin, Ph.D., Jennifer Johnson, M.S., Kin H. Lau, Ph.D., na Galen Hostetter, M.D., wa VAI.""" VAI's Genomics Core, Pathology na Biorepository Core, Optical Imaging Core na Vivarium Core pia ilichangia kazi hii. Utafiti ulioelezwa katika chapisho hili uliungwa mkono na Taasisi ya Van Andel na Taasisi ya Kitaifa ya Saratani ya Taasisi za Kitaifa za Afya chini ya tuzo ya No. R0234595 (Pfeifer) Maudhui ni wajibu pekee wa waandishi na si lazima kuwakilisha maoni rasmi ya Taasisi za Taifa za Afya. Banner picha mikopo: Courtesy ya Adobe Stock <unk> Catalin. Taasisi ya Van Andel (VAN) ni taasisi ya kitaaluma ya kimataifa iliyojengwa kwa lengo la kuboresha afya na maisha ya vizazi vya sasa na vijavyo kupitia utafiti wa kisasa wa biomedical na matoleo ya elimu ya ubunifu. Ilianzishwa katika Grand Rapids, Michigan, mnamo 1996 na familia ya Van Andel, VAI sasa ni nyumbani kwa wanasayansi karibu 500, waalimu na wafanyikazi wa msaada, ambao wanafanya kazi na idadi inayoongezeka ya washirika wa kitaifa na wa kimataifa kukuza uvumbuzi. Wanasayansi wa Taasisi hiyo hujifunza chanzo cha kansa, Parkinson na magonjwa mengine na kutafsiri matokeo yao katika mikakati ya kuzuia na kutibu. Wanafunzi wetu wanaendeleza mbinu za uchunguzi kwa elimu ya K-12 kusaidia wanafunzi na walimu kuandaa kizazi kijacho cha watatuaji wa tatizo, wakati Shule yetu ya Kujifunza inatoa programu ya PhD ya utafiti wa kina katika biolojia ya molekuli na ya seli.